bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoxic Induction of Exosome Uptake through Proteoglycan-Dependent Endocytosis Fuels the Lipid Droplet Phenotype in Glioma
Authors: Cerezo-Magaña Myriam , Christianson Helena C. , van Kuppevelt Toin H. , Forsberg-Nilsson Karin , Belting Mattias
Published: December 2020

As an adaptive response to hypoxic stress, aggressive tumors rewire their metabolic phenotype into increased malignant behavior through extracellular lipid scavenging and storage in lipid droplets (LD). However, the underlying mechanisms and potential lipid source retrieved in the hypoxic tumor microenvironment remain poorly understood. Here, we show that exosome-like extracellular vesicles (EV), known as influential messengers in the tumor microenvironment, may also serve anabolic functions by transforming hypoxic, patient-derived human glioblastoma cell lines into the LD+ phenotype. EVs were internalized via a hypoxia-sensitive, endocytic mechanism that fueled LD formation through direct lipid transfer, and independently of fatty acid synthase activity. EVs can enter cells through multiple and yet ill-defined pathways. On a mechanistic level, we found that hypoxia-mediated EV uptake depends on increased heparan sulfate proteoglycan (HSPG) endocytosis that preferentially followed the lipid raft pathway. The functional relevance of HSPG was evidenced by the reversal of EV-mediated LD loading by targeting of HSPG receptor function.

Implications:

Together, our data extend the multifaceted role of EVs in cancer biology by showing their LD-inducing capacity in hypoxic glioma cells. Moreover, these findings highlight a potential function for HSPG-mediated endocytosis as a salvage pathway for EV retrieval during tumor stress conditions.
The Heme-Regulated Inhibitor Pathway Modulates Susceptibility of Poor Prognosis B-Lineage Acute Leukemia to BH3-Mimetics
Authors: Smith Kaitlyn H. , Budhraja Amit , Lynch John , Roberts Kathryn , Panetta John C. , Connelly Jon P. , Turnis Meghan E. , Pruett-Miller Shondra M. , Schuetz John D. , Mullighan Charles G. , Opferman Joseph T.
Published: December 2020

Antiapoptotic MCL1 is one of the most frequently amplified genes in human cancers and elevated expression confers resistance to many therapeutics including the BH3-mimetic agents ABT-199 and ABT-263. The antimalarial, dihydroartemisinin (DHA) translationally represses MCL-1 and synergizes with BH3-mimetics. To explore how DHA represses MCL-1, a genome-wide CRISPR screen identified that loss of genes in the heme synthesis pathway renders mouse BCR-ABL+ B-ALL cells resistant to DHA-induced death. Mechanistically, DHA disrupts the interaction between heme and the eIF2α kinase heme-regulated inhibitor (HRI) triggering the integrated stress response. Genetic ablation of Eif2ak1, which encodes HRI, blocks MCL-1 repression in response to DHA treatment and represses the synergistic killing of DHA and BH3-mimetics compared with wild-type leukemia. Furthermore, BTdCPU, a small-molecule activator of HRI, similarly triggers MCL-1 repression and synergizes with BH3-mimetics in mouse and human leukemia including both Ph+ and Ph-like B-ALL. Finally, combinatorial treatment of leukemia bearing mice with both BTdCPU and a BH3-mimetic extended survival and repressed MCL-1 in vivo. These findings reveal for the first time that the HRI-dependent cellular heme-sensing pathway can modulate apoptosis in leukemic cells by repressing MCL-1 and increasing their responsiveness to BH3-mimetics. This signaling pathway could represent a generalizable mechanism for repressing MCL-1 expression in malignant cells and sensitizing them to available therapeutics.

Implications:

The HRI-dependent cellular heme-sensing pathway can modulate apoptotic sensitivity in leukemic cells by repressing antiapoptotic MCL-1 and increasing their responsiveness to BH3-mimetics.
Protein Arginine Methyltransferase 5 (PRMT5) and the ERK1/2 & PI3K Pathways: A Case for PRMT5 Inhibition and Combination Therapies in Cancer
Authors: Sapir Tzuriel , Shifteh David , Pahmer Moshe , Goel Sanjay , Maitra Radhashree
Published: December 2020

The ERK1/2 (RAS, RAF, MEK, ERK) and PI3K (PI3K, AKT, mTOR, PTEN) pathways are the chief signaling pathways for cellular proliferation, survival, and differentiation. Overactivation and hyperphosphorylation of the ERK1/2 & PI3K pathways is frequently observed in cancer and is associated with poor patient prognosis. While it is well known that genetic alterations lead to the dysregulation of the ERK1/2 & PI3K pathways, increasing evidence showcase that epigenetic alterations also play a major role in the regulation of the ERK1/2 & PI3K pathways. Protein Arginine Methyltransferase 5 (PRMT5) is a posttranslational modifier for multiple cellular processes, which is currently being tested as a therapeutic target for cancer. PRMT5 has been shown to be overexpressed in many types of cancers, as well as negatively correlated with patient survival. Numerous studies are indicating that as a posttranslational modifier, PRMT5 is extensively involved in regulating the ERK1/2 & PI3K pathways. In addition, a large number of in vitro and in vivo studies are demonstrating that PRMT5 inhibition, as well as PRMT5 and ERK1/2 & PI3K combination therapies, show significant therapeutic effects in many cancer types. In this review, we explore the vast interactions that PRMT5 has with the ERK1/2 & PI3K pathways, and we make the case for further testing of PRMT5 inhibition, as well as PRMT5 and ERK1/2 & PI3K combination therapies, for the treatment of cancer.
A Therapeutic Strategy for Preferential Targeting of TET2-Mutant and TET Dioxygenase–Deficient Cells in Myeloid Neoplasms
Authors: Guan Yihong , Tiwari Anand D. , Phillips James G. , Hasipek Metis , Grabowski Dale R. , Pagliuca Simona , Gopal Priyanka , Kerr Cassandra M. , Adema Vera , Radivoyevitch Tomas , Parker Yvonne , Lindner Daniel J. , Meggendorfer Manja , Abazeed Mohamed , Sekeres Mikkeal A. , Mian Omar Y. , Haferlach Torsten , Maciejewski Jaroslaw P. , Jha Babal K.
Published: December 2020

TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant–derived 2-hydroxyglutarate is synthetically lethal to TET dioxygenase–deficient cells. In addition, a TET-selective small-molecule inhibitor decreases cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant but not normal hematopoietic precursor cells in vitro and in vivo. Although TET inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells are, unlike mutations, reversible. Treatment with TET inhibitor suppresses the clonal evolution of TET2-mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of targeted agents in TET2-mutant neoplasia.

Significance:

Loss-of-function somatic TET2 mutations are among the most frequent lesions in myeloid neoplasms and associated disorders. Here we report a strategy for selective targeting of residual TET dioxygenase activity in TET-deficient clones that results in restriction of clonal evolution in vitro and in vivo.

See related video: https://aacrjournals.org/webinar-minimal-tet-activity-targetable-vulnerability-tet2-and-neomorphic-idh12-mutant
Associations between Polymorphisms in the IL-1 Gene and the Risk of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Evidence from a Meta-Analysis
Authors: Zhu Lin , Chen Peng , Sun Xuanjing , Zhang Shuo
Published: December 2020

Background: Previous studies on polymorphisms in interleukin-1 (IL-1) and the risk of rheumatoid arthritis (RA)/systemic lupus erythematosus (SLE) yielded inconsistent results. Objectives: The authors performed this meta-analysis to more robustly evaluate associations between polymorphisms in the IL-1 gene and the risk of RA/SLE. Methods: MEDLINE, Embase, Web of Science, Wanfang, VIP, and CNKI were systematically searched for eligible studies, and 34 relevant studies were finally selected to be eligible for inclusion. Results: We found that IL-1A +4845G/T polymorphism was significantly associated with the risk of RA in the overall population (dominant comparison: p = 0.02; overdominant comparison: p = 0.05; allele comparison: p = 0.04), whereas IL-1B +3954C/T polymorphism was significantly associated with the risk of RA in the overall population (overdominant comparison: p = 0.03; allele comparison: p = 0.01) and Asians (recessive comparison: p = 0.007; allele comparison: p = 0.002). In addition, we found that IL-1A –889C/T polymorphism was significantly associated with the risk of SLE in Caucasians (allele comparison: p = 0.04), IL-1B –31T/C polymorphism was significantly associated with the risk of SLE in the overall population (recessive comparison: p = 0.04), and IL-1B –511C/T polymorphism was significantly associated with the risk of SLE in Asians (recessive comparison: p = 0.01; allele comparison: p = 0.03). Conclusions: This meta-analysis suggests that IL-1A +4845G/T and IL-1B +3954C/T polymorphisms may influence the risk of RA, whereas IL-1A –889C/T, IL-1B –31T/C, and IL-1B –511C/T polymorphisms may influence the risk of SLE.
Use of Composite End Points in Early and Intermediate Age-Related Macular Degeneration Clinical Trials: State-of-the-Art and Future Directions
Authors: Terheyden Jan Henrik , Schmitz-Valckenberg Steffen , Crabb David P. , Dunbar Hannah , Luhmann Ulrich F.O. , Behning Charlotte , Schmid Matthias , Silva Rufino , Cunha-Vaz José , Tufail Adnan , Weissgerber Georges , Leal Sergio , Holz Frank G. , Finger Robert P. ,   on behalf of the MACUSTAR Consortium
Published: December 2020

The slow progression of early age-related macular degeneration (AMD) stages to advanced AMD requires the use of surrogate end points in clinical trials. The use of combined end points may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite end points as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite end points used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite end point categories were: combined structural and functional end points, combined structural end points, combined functional end points and combined multicategorical end points. The majority of the studies included binary composite end points. There was a lack of sensitivity analyses of different end points against accepted outcomes (i.e., progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined end points in clinical studies of early stages of AMD exists, and no surrogate end points have been accepted for AMD progression.
Associations Between Female Sex, Sarcomere Variants, and Clinical Outcomes in Hypertrophic Cardiomyopathy
Authors: Lakdawala Neal K. , Olivotto Iacopo , Day Sharlene M. , Han Larry , Ashley Euan A. , Michels Michelle , Ingles Jodie , Semsarian Christopher , Jacoby Daniel , Jefferies John L. , Colan Steven D. , Pereira Alexandre C. , Rossano Joseph W. , Wittekind Sam , Ware James S. , Saberi Sara , Helms Adam S. , Cirino Allison L. , Leinwand Leslie A. , Seidman Christine E. , Ho Carolyn Y.
Published: December 2020

Background:

The impact of sex on phenotypic expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohorts.

Methods:

Retrospective cohort study from an international registry of patients receiving care at experienced HCM centers. Sex-based differences in baseline characteristics and clinical outcomes were assessed.

Results:

Of 5873 patients (3788 genotyped), 2226 (37.9%) were women. At baseline, women were older (49.0±19.9 versus 42.9±18.4 years,
P
<0.001) and more likely to have pathogenic/likely pathogenic sarcomeric variants (HCM patients with a sarcomere mutation; 51% versus 43%,
P
<0.001) despite equivalent utilization of genetic testing. Age at diagnosis varied by sex and genotype despite similar distribution of causal genes. Women were 3.6 to 7.1 years older at diagnosis (
P
<0.02) except for patients with
MYH7
variants where age at diagnosis was comparable for women and men (n=492; 34.8±19.2 versus 33.3±16.8 years,
P
=0.39). Over 7.7 median years of follow-up, New York Heart Association III-IV heart failure was more common in women (hazard ratio, 1.87 [CI, 1.48–2.36],
P
<0.001), after controlling for their higher burden of symptoms and outflow tract obstruction at baseline, reduced ejection fraction, HCM patients with a sarcomere mutation, age, and hypertension. All-cause mortality was increased in women (hazard ratio, 1.50 [CI, 1.13–1.99],
P
<0.01) but neither implantable cardioverter-defibrillator utilization nor ventricular arrhythmia varied by sex.

Conclusions:

In HCM, women are older at diagnosis, partly modified by genetic substrate. Regardless of genotype, women were at higher risk of mortality and developing severe heart failure symptoms. This points to a sex-effect on long-term myocardial performance in HCM, which should be investigated further.
Economic Evaluation of Catheter Ablation of Atrial Fibrillation in Patients with Heart Failure With Reduced Ejection Fraction
Authors: Chew Derek S. , Loring Zak , Anand Jatin , Fudim Marat , Lowenstern Angela , Rymer Jennifer A. , Weimer Kristin E.D. , Atwater Brett D. , DeVore Adam D. , Exner Derek V. , Noseworthy Peter A. , Yancy Clyde W. , Mark Daniel B. , Piccini Jonathan P.
Published: December 2020

Background:

Randomized clinical trials have demonstrated that catheter ablation for atrial fibrillation in patients with heart failure with reduced ejection fraction may improve survival and other cardiovascular outcomes.

Methods:

We constructed a decision-analytic Markov model to estimate the costs and benefits of catheter ablation and medical management in patients with symptomatic heart failure with reduced ejection fraction (left ventricular ejection fraction ≤35%) and atrial fibrillation over a lifetime horizon. Evidence from the published literature informed the model inputs, including clinical effectiveness data from meta-analyses. Probabilistic and deterministic sensitivity analyses were performed. A 3% discount rate was applied to both future costs and benefits. The primary outcome was the incremental cost-effectiveness ratio assessed from the US health care sector perspective.

Results:

Catheter ablation was associated with 6.47 (95% CI, 5.89–6.93) quality-adjusted life years (QALYs) and a total cost of $105 657 (95% CI, $55 311–$191 934; 2018 US dollars), compared with 5.30 (95% CI, 5.20–5.39) QALYs and $63 040 (95% CI, $37 624–$102 260) for medical management. The incremental cost-effectiveness ratio for catheter ablation compared with medical management was $38 496 (95% CI, $5583–$117 510) per QALY gained. Model inputs with the greatest variation on incremental cost-effectiveness ratio estimates were the cost of ablation and the effect of catheter ablation on mortality reduction. When assuming a more conservative estimate of the treatment effect of catheter ablation on mortality (hazard ratio of 0.86), the estimated incremental cost-effectiveness ratio was $74 403 per QALY gained. At a willingness-to-pay threshold of $100 000 per QALY gained, atrial fibrillation ablation was found to be economically favorable compared with medical management in 95% of simulations.

Conclusions:

Catheter ablation in patients with heart failure with reduced ejection fraction patients and atrial fibrillation may be considered economically attractive at current benchmarks for societal willingness-to-pay in the United States.
Site-1 Protease-Derived Soluble (Pro)Renin Receptor Contributes to Angiotensin II–Induced Hypertension in Mice
Authors: Feng Ye , Peng Kexin , Luo Renfei , Wang Fei , Yang Tianxin
Published: December 2020

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II–induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II–induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II–induced hypertension through enhancement of intrarenal renin level and activation of ENaC.
Masked Uncontrolled Hypertension Is Accompanied by Increased Out-of-Clinic Aldosterone Secretion
Authors: Siddiqui Mohammed , Judd Eric K. , Zhang Bin , Dudenbostel Tanja , Carey Robert M. , Oparil Suzanne , Calhoun David A.
Published: December 2020

Masked uncontrolled hypertension (MUCH) in treated patients is defined as controlled office blood pressure (BP) but uncontrolled out-of-clinic ambulatory BP. Previously, we have shown that patients with MUCH have evidence of heightened out-of-clinic sympathetic nervous system activity. The aim is to test the hypothesis that MUCH patients have higher aldosterone secretion compared with patients with true controlled hypertension. Two hundred twenty-two patients were recruited after having controlled office BP readings at ≥3 clinic visits. Patients taking MR (mineralocorticoid receptor) antagonists and epithelial sodium channel blockers were excluded. All patients were evaluated by clinic automated office BP and morning serum aldosterone and plasma renin activity. Out-of-clinic ambulatory BP monitoring and 24-hour urinary aldosterone, catecholamines, and metanephrines were also measured. Sixty-four patients had MUCH, and the remaining 48 patients had true controlled hypertension. MUCH patients had significantly higher out-of-clinic levels of 24-hour urinary aldosterone, catecholamines, and metanephrines compared with true controlled hypertension. The 2 groups did not differ in serum aldosterone, plasma renin activity, or aldosterone-renin ratio collected in clinic. In addition, 32.8% of MUCH patients had high out-of-clinic 24-hour urinary aldosterone (≥12 µg) but normal clinic serum aldosterone (<15 ng/dL) and aldosterone-renin ratio (<20). Further, in correlation matrix analysis, higher 24-hour urinary catecholamines and metanephrines were associated with higher 24-hour urinary aldosterone and plasma renin activity levels in MUCH patients. Patients with MUCH have higher out-of-clinic urinary aldosterone levels compared with patients with true controlled hypertension. This study suggests that patients with MUCH likely have higher out-of-clinic sympathetic nervous system tone increases aldosterone secretion mediated by increased renin release that may contribute to their higher out-of-clinic BP.
Intraindividual Variability of Aldosterone Concentrations in Primary Aldosteronism
Authors: Yozamp Nicholas , Hundemer Gregory L. , Moussa Marwan , Underhill Jonathan , Fudim Tali , Sacks Barry , Vaidya Anand
Published: December 2020

Primary aldosteronism is an underdiagnosed cause of hypertension. Although inadequate screening is one reason for underdiagnosis, another important contributor is that clinicians may inappropriately exclude the diagnosis when screening aldosterone concentrations fall below traditionally established thresholds. We evaluated the intraindividual variability in screening aldosterone concentrations and aldosterone-to-renin ratios, and how this variability could impact case detection, among 51 patients with confirmed primary aldosteronism who had 2 or more screening measurements of renin and aldosterone on different days. There were a total of 137 screening measurements with a mean of 3 (range 2–6) per patient. The mean intraindividual variability, expressed as coefficients of variation, was 31% for aldosterone and 45% for the aldosterone-to-renin ratio. Aldosterone concentrations ranged from 4.9 to 51 ng/dL; 49% of patients had at least one aldosterone measurement below 15 ng/dL, 29% had at least 2 aldosterone measurements below 15 ng/dL, and 29% had at least one measurement below 10 ng/dL. Individual aldosterone-to-renin ratios ranged from 8.2 to 427 ng/dL per ng/mL·hour; 57% had at least one ratio below 30 ng/dL per ng/mL·hour, 27% had at least 2 ratios below 30 ng/dL per ng/mL·hour, and 24% had at least one ratio below 20 ng/dL per ng/mL·hour. Aldosterone concentrations and aldosterone-to-renin ratios are highly variable in patients with primary aldosteronism, with many screening values falling below conventionally accepted diagnostic thresholds. The diagnostic yield for primary aldosteronism may be substantially increased by recalibrating the definition of a positive screen to include more liberal thresholds for aldosterone and the aldosterone-to-renin ratio.
Association of Diagnostic Coding‐Based Frailty and Outcomes in Patients With Heart Failure: A Report From the Veterans Affairs Health System
Authors: Kohsaka Shun , Sandhu Alexander T. , Parizo Justin T. , Shoji Satoshi , Kumamamru Hiraku , Heidenreich Paul A.
Published: December 2020

Background

The aim of this study was to determine whether frailty is associated with increased admission and mortality risk in the setting of heart failure.

Methods and Results

This retrospective cohort analysis included patients treated within the Veterans Affairs Health System who had
International Classification of Diseases, Ninth Revision
(
ICD‐9
) codes for heart failure on 2 or more dates over a 2‐year period. The clinical variables identifiable in claims data, such as demographic variables and markers of physical and cognitive dysfunction, were used to identify patients meeting the frailty phenotype. Of 388 785 extracted patients with coding of heart failure between 2015 and 2018, 163 085 patients (41.9%) with ejection fraction (EF) measurement were included in the present analysis (38.3% with reduced EF and 61.7% with preserved EF). There were 16 660 patients (10.2%) who were identified as frail (9.1% in heart failure with reduced EF and 10.9% in heart failure with preserved EF). Frail patients were older, more often depressed, and were likely to have been admitted in the previous year. One‐year all‐cause mortality rate was 9.7% and 28.1%, and admission rate was 58.1% and 79.5% for nonfrail and frail patients, respectively. Frailty was associated with mortality and admission risk compared with the nonfrail group (adjusted odds ratio [OR], 1.71; 95% CI, 1.65–1.77 for mortality; adjusted OR, 1.29; 95% CI, 1.24–1.34 for admission) independent of EF.

Conclusions

Frailty based on diagnostic coding was associated with particularly higher risk of mortality despite adjustment for known clinical variables. Our findings underscore the importance of nontraditional parameters in the prognostic assessment.
Global Fractional Flow Reserve Value Predicts 5‐Year Outcomes in Patients With Coronary Atherosclerosis But Without Ischemia
Authors: Fournier Stephane , Collet Carlos , Xaplanteris Panagiotis , Zimmermann Frederik M. , Toth Gabor G. , Tonino Pim A. L. , Pijls Nico H. J. , Colaiori Iginio , Di Gioia Giuseppe , Barbato Emanuele , Jüni Peter , Fearon William F. , De Bruyne Bernard
Published: December 2020

Background

Global fractional flow reserve (FFR) (ie, the sum of the FFR values in the 3 major coronary arteries) is a physiologic correlate of global atherosclerotic burden. The objective of the present study was to investigate the value of global FFR in predicting long‐term clinical outcome of patients with stable coronary artery disease but no ischemia‐inducing stenosis.

Methods and Results

We studied major adverse cardiovascular events (MACEs: all‐cause death, myocardial infarction, and any revascularization) after 5 years in 1122 patients without significant stenosis (all FFR >0.80; n=275) or with at least 1 significant stenosis successfully treated by percutaneous coronary intervention (ie, post–percutaneous coronary intervention FFR >0.80; n=847). The patients were stratified into low, mid, or high tertiles of global FFR (≤2.80, 2.80–2.88, and ≥2.88). Patients in the lowest tertile of global FFR showed the highest 5‐year MACE rate compared with those in the mid or high tertile of global FFR (27.5% versus 22.0% and 20.9%, respectively; log‐rank
P
=0.040). The higher 5‐year MACE rate was mainly driven by a higher rate of revascularization in the low global FFR group (16.4% versus 11.3% and 11.8%, respectively; log‐rank
P
=0.038). In a multivariable model, an increase in global FFR of 0.1 unit was associated with a significant reduction in the rates of MACE (hazard ratio [HR], 0.988; 95% CI, 0.977–0.998;
P
=0.023), myocardial infarction (HR, 0.982; 95% CI, 0.966–0.998;
P
=0.032), and revascularization (HR, 0.985; 95% CI, 0.972–0.999;
P
=0.040).

Conclusions

Even in the absence of ischemia‐producing stenoses, patients with a low global FFR, physiologic correlate of global atherosclerotic burden, present a higher risk of MACE at 5‐year follow‐up.
Imaging Predictors of Neurologic Outcome After Pediatric Arterial Ischemic Stroke
Authors: Jiang Bin , Hills Nancy K. , Forsyth Rob , Jordan Lori C. , Slim Mahmoud , Pavlakis Steven G. , Freidman Neil , Dlamini Nomazulu , Farooq Osman , Li Ying , Zhu Guangming , Fullerton Heather , Wintermark Max , Lo Warren D. , Dowling M.M. , Benedict S.L. , Bernard T.J. , Fox C.K. , deVeber G. , Friedman N.R. , Lo W. , Ichord R.N. , Tan M. , Mackay M. , Kirton A. , Hernandez Chavez M.I. , Humphreys P. , Sultan S. , Rivkin M.J. , Yeh A. , Rafay M.F. , Titomanlio L. , Kovacevic G.S. , Yager J.Y. , Amlie-Lefond C. , Condie J. , Kneen R. , Bjornson B. , Pergami P. , Zou L.P. , Elbers J. , Abdalla A. , Chan A.K. , Carpenter J.L. , Wong V.C. , Kirkham F.
Published: December 2020

Background and Purpose:

To assess whether initial imaging characteristics independently predict 1-year neurological outcomes in childhood arterial ischemic stroke patients.

Methods:

We used prospectively collected demographic and clinical data, imaging data, and 1-year outcomes from the VIPS study (Vascular Effects of Infection in Pediatric Stroke). In 288 patients with first-time stroke, we measured infarct volume and location on the acute magnetic resonance imaging studies and hemorrhagic transformation on brain imaging studies during the acute presentation. Neurological outcome was assessed with the Pediatric Stroke Outcome Measure. We used univariate and multivariable ordinal logistic regression models to test the association between imaging characteristics and outcome.

Results:

Univariate analysis demonstrated that infarcts involving uncinate fasciculus, angular gyrus, insular cortex, or that extended from cortex to the subcortical nuclei were significantly associated with poorer outcomes with odds ratios ranging from 1.95 to 3.95. All locations except the insular cortex remained significant predictors of poor outcome on multivariable analysis. When infarct volume was added to the model, the locations did not remain significant. Larger infarct volumes and younger age at stroke onset were significantly associated with poorer outcome, but the strength of the relationships was weak. Hemorrhagic transformation did not predict outcome.

Conclusions:

In the largest pediatric arterial ischemic stroke cohort collected to date, we showed that larger infarct volume and younger age at stroke were associated with poorer outcomes. We made the novel observation that the strength of these associations was modest and limits the ability to use these characteristics to predict outcome in children. Infarcts affecting specific locations were significantly associated with poorer outcomes in univariate and multivariable analyses but lost significance when adjusted for infarct volume. Our findings suggest that infarcts that disrupt critical networks have a disproportionate impact upon outcome after childhood arterial ischemic stroke.
External Validation of Five Scores to Predict Stroke-Associated Pneumonia and the Role of Selected Blood Biomarkers
Authors: Hotter Benjamin , Hoffmann Sarah , Ulm Lena , Meisel Christian , Bustamante Alejandro , Montaner Joan , Katan Mira , Smith Craig J. , Meisel Andreas
Published: December 2020

Background and Purpose:

Several clinical scoring systems as well as biomarkers have been proposed to predict stroke-associated pneumonia (SAP). We aimed to externally and competitively validate SAP scores and hypothesized that 5 selected biomarkers would improve performance of these scores.

Methods:

We pooled the clinical data of 2 acute stroke studies with identical data assessment: STRAWINSKI and PREDICT. Biomarkers (ultrasensitive procalcitonin; mid-regional proadrenomedullin; mid-regional proatrionatriuretic peptide; ultrasensitive copeptin; C-terminal proendothelin) were measured from hospital admission serum samples. A literature search was performed to identify SAP prediction scores. We then calculated multivariate regression models with the individual scores and the biomarkers. Areas under receiver operating characteristic curves were used to compare discrimination of these scores and models.

Results:

The combined cohort consisted of 683 cases, of which 573 had available backup samples to perform the biomarker analysis. Literature search identified 9 SAP prediction scores. Our data set enabled us to calculate 5 of these scores. The scores had area under receiver operating characteristic curve of 0.543 to 0.651 for physician determined SAP, 0.574 to 0.685 for probable and 0.689 to 0.811 for definite SAP according to Pneumonia in Stroke Consensus group criteria. Multivariate models of the scores with biomarkers improved virtually all predictions, but mostly in the range of an area under receiver operating characteristic curve delta of 0.05.

Conclusions:

All SAP prediction scores identified patients who would develop SAP with fair to strong capabilities, with better discrimination when stricter criteria for SAP diagnosis were applied. The selected biomarkers provided only limited added predictive value, currently not warranting addition of these markers to prediction models.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01264549 and NCT01079728.
Electroencephalographic Study on Sensory Integration in Visually Induced Postural Sway
Authors: Kagawa Takahiro , Makeig Scott , Miyakoshi Makoto
Published: December 2020

A periodically reversing optic flow animation, experienced while standing, induces an involuntary sway termed visually induced postural sway (VIPS). Interestingly, VIPS is suppressed during light finger touch to a stationary object. Here, we explored whether VIPS is mediated by parietal field activity in the dorsal visual stream as well as by activity in early visual areas, as has been suggested. We performed a mobile brain/body imaging study using high-density electroencephalographic recording from human participants (11 men and 3 women) standing during exposure to periodically reversing optic flow with and without light finger touch to a stable surface. We also performed recording their visuo-postural tracking movements as a typical visually guided movement to explore differences of cortical process of VIPS from the voluntary visuomotor process involving the dorsal stream. In the visuo-postural tracking condition, the participants moved their center of pressure in time with a slowly oscillating (expanding, shrinking) target rectangle. Source-resolved results showed that alpha band (8–13 Hz) activity in the medial and right occipital cortex during VIPS was modulated by the direction and velocity of optic flow and increased significantly during light finger touch. However, source-resolved potentials from the parietal association cortex showed no such modulation. During voluntary postural sway with feedback (but no visual flow) in which the dorsal stream is involved, sensorimotor areas produced more theta band (4–7 Hz) and less beta band (14–35 Hz) activity than during involuntary VIPS. These results suggest that VIPS involves cortical field dynamic changes in the early visual cortex rather than in the posterior parietal cortex of the visual dorsal stream.
Descartes and the Dutch: Botanical Experimentation in the Early Modern Period
Authors: Baldassarri Fabrizio
Published: December 2020

Early modern study of plants blossomed in a network of observation, exchanges, collaborations, and epistolary discussions. Following Baconian methodology, Dutch scholars combined the labor of listing and describing plants with botanical experimentation. This empirical approach was a suitable context for Descartes, who exchanged information and performed observations on plants in collaboration with Dutch experimenters. In this article, I focus on (1) the reception of a few botanical experiments of Bacon’s Sylva Sylvarum in Huygens and Reneri, with whom Descartes was in contact, and (2) Descartes’ collaboration with Reneri. While performing observations on plants together, Reneri acquired Descartes’ theoretical framework (as it arises in his disputations) and influenced the latter with a Baconian approach to the study of living nature. This combination of experimental knowledge and a theoretical framework shaped a Cartesian study of plants, as it later surfaced in Regius and ultimately paved the way to a modern science of plants.
The wild bees (Hymenoptera: Apoidea) of Morocco
Authors: LHOMME PATRICK , MICHEZ DENIS , CHRISTMANN STEFANIE , SCHEUCHL ERWIN , ABDOUNI INSAFE EL , HAMROUD LAILA , IHSANE OUMAYMA , SENTIL AHLAM , SMAILI MOULAY CHRIF , SCHWARZ MAXIMILIAN , DATHE HOLGER H. , STRAKA JAKUB , PAULY ALAIN , SCHMID-EGGER CHRISTIAN , PATINY SEBASTIEN , TERZO MICHAEL , MÜLLER ANDREAS , PRAZ CHRISTOPHE , RISCH STEPHAN , KASPAREK MAX , KUHLMANN MICHAEL , WOOD THOMAS J. , BOGUSCH PETR , ASCHER JOHN S. , RASMONT PIERRE
Published: December 2020

Morocco is a well known hot-spot of biodiversity in the Mediterranean basin. While some taxa like vascular plants are relatively well recorded, important groups of pollinators like bees are still understudied. This article presents an updated checklist of the bee species of Morocco and includes a summary of global and regional distribution of each species. A total of 961 species belonging to six bee families and 68 genera are recorded: Andrenidae (8 genera, 217 species); Apidae (15 genera, 241 species); Colletidae (2 genera, 74 species), Halictidae (12 genera, 144 species), Megachilidae (28 genera, 271 species) and Melittidae (3 genera, 14 species). Among them, 67 species are recorded for the first time in Morocco. Around 70% of the bee fauna of Morocco consists of widespread Palaearctic species. Only 18% of Moroccan species recorded are restricted to North Africa and 8% are Moroccan single-country endemics (81 species). Afrotropical elements in the Moroccan fauna are few, with only 3% of Morocco species co-occuring in that region. This checklist is intended to stimulate new regional research on bees including their taxonomy and biogeography. As many groups of bees have been understudied, discovery of new species for science and new records for the country can be expected. Additional research including inventorying, monitoring, and integrative taxonomic studies are needed to develop a comprehensive strategy for bee conservation in Morocco.
Which Combinations of Environmental Conditions and Microphysical Parameter Values Produce a Given Orographic Precipitation Distribution?
Authors: Morales Annareli , Posselt Derek J. , Morrison Hugh
Published: December 2020

This study applies an idealized modeling framework, alongside a Bayesian Markov chain Monte Carlo (MCMC) algorithm, to explore which combinations of upstream environmental conditions and cloud microphysical parameter values can produce a particular precipitation distribution over an idealized two-dimensional, bell-shaped mountain. Simulations focus on orographic precipitation produced when an atmospheric river interacts with topography. MCMC-based analysis reveals that different combinations of parameter values produce a similar precipitation distribution, with the most influential parameters being relative humidity (RH), horizontal wind speed (U), surface potential temperature (θsfc), and the snow fall speed coefficient (As). RH, U, and As exhibit interdependence: changes in one or more of these factors can be mitigated by compensating changes in the other(s) to produce similar orographic precipitation rates. The results also indicate that the parameter sensitivities and relationships can vary for spatial subregions and given different environmental conditions. In particular, high θsfc values are more likely to produce the target precipitation rate and spatial distribution, and thus the ensemble of simulations shows a preference for liquid precipitation at the surface. The results presented here highlight the complexity of orographic precipitation controls, and have implications for flood and water management, observational efforts, and climate change.
Turbulence Driven by Reflected Internal Tides in a Supercritical Submarine Canyon
Authors: Hamann Madeleine M. , Alford Matthew H. , Lucas Andrew J. , Waterhouse Amy F. , Voet Gunnar
Published: December 2020

The La Jolla Canyon System (LJCS) is a small, steep, shelf-incising canyon offshore of San Diego, California. Observations conducted in the fall of 2016 capture the dynamics of internal tides and turbulence patterns. Semidiurnal (D2) energy flux was oriented up-canyon; 62% ± 20% of the signal was contained in mode 1 at the offshore mooring. The observed mode-1 D2 tide was partly standing based on the ratio of group speed times energy cgE and energy flux F. Enhanced dissipation occurred near the canyon head at middepths associated with elevated strain arising from the standing wave pattern. Modes 2–5 were progressive, and energy fluxes associated with these modes were oriented down-canyon, suggesting that incident mode-1 waves were back-reflected and scattered. Flux integrated over all modes across a given canyon cross section was always onshore and generally decreased moving shoreward (from 240 ± 15 to 5 ± 0.3 kW), with a 50-kW increase in flux occurring on a section inshore of the canyon’s major bend, possibly due to reflection of incident waves from the supercritical sidewalls of the bend. Flux convergence from canyon mouth to head was balanced by the volume-integrated dissipation observed. By comparing energy budgets from a global compendium of canyons with sufficient observations (six in total), a similar balance was found. One exception was Juan de Fuca Canyon, where such a balance was not found, likely due to its nontidal flows. These results suggest that internal tides incident at the mouth of a canyon system are dissipated therein rather than leaking over the sidewalls or siphoning energy to other wave frequencies.
Influence of geometric imperfection of journal on the performance of porous hybrid journal bearing under turbulent condition
Authors: Singh Anil , Sharma Satish C
Published: December 2020

The present work deals with numerical investigation into geometric imperfection (bellmouth, undulation and barrel shape) of the journal on performance of a porous hybrid journal bearing system (PHJBs) operating under turbulent flow condition. The Reynolds equation governing the flow of lubricant in the bearing clearance space is modified by using the turbulent lubrication theory proposed by Constantinescu’s. The bearing performance parameters are numerically computed using FEM. The effects of geometric irregularities, turbulent flow condition, and permeability parameters have been investigated on the performance of PHJBs. The theoretically obtained results indicates that the combined effect of turbulent flow condition and geometric imperfection offers enhanced values of [Formula: see text] and rotor dynamic coefficients (stiffness and damping coefficients).
Thermal mixing effect and heat transfer in U-shaped notch on the mechanical seal face
Authors: Qiu Yujie , Meng Xiangkai , Liang Yangyang , Peng Xudong
Published: December 2020

A three-dimensional thermohydrodynamic (THD) model of a notched mechanical seal is developed based on the commercial software ANSYS Fluent. The flow behavior of hot and cold fluid in and around the notch, namely, the thermal mixing effect, is detailly analyzed. The heat transfer between the notch fluid and the seal rings as well as the cooling effect mechanism of the notch are discussed. Finally, a parametric analysis is conducted to study the effect of notch size, rotational speed and seal gap on heat transport. The results show that the notch fluid locally decreases the notched stator face temperature around the notch boundaries. The reflux occurs between the sealing chamber and notch, which brings the most cooling effect to the notch. The notch depth and width have a significant effect on the heat transfer between the fluid and sealing rings. Because of the non-simplified THD model, the proposed research provides increased reliability of understanding the flow and temperature behavior in the notch.
The evolution of the Sesia Zone (Western Alps) from Carboniferous to Cretaceous: insights from zircon and allanite geochronology
Authors: Vho Alice , Rubatto Daniela , Lanari Pierre , Regis Daniele
Published: December 2020

Microscale dating of distinct domains in minerals that contain relics of multiple metamorphic events is a key tool to characterize the polyphase evolution of complex metamorphic terranes. Zircon and allanite from five metasediments and five metaintrusive high-pressure (HP) rocks from the Eclogite Micaschist Complex of the Sesia Zone were dated by SIMS and LA-ICP-MS. In the metasediments, zircon systematically preserves detrital cores and one or two metamorphic overgrowths. An early Permian age is obtained for the first zircon rim in metasediments from the localities of Malone Valley, Chiusella Valley and Monte Mucrone (292 ± 11, 278.8 ± 3.6 and 285.9 ± 2.9 Ma, respectively). In the Malone Valley and Monte Mucrone samples, the early Permian ages are attributed to high-temperature metamorphism and coincide with the crystallization ages of associated mafic and felsic intrusions. This implies that magmatism and metamorphism were coeval and associated to the same tectono-metamorphic extensional event. In the Malone Valley, allanite from a metasediment is dated at 241.1 ± 6.1 Ma and this age is tentatively attributed to a metasomatic/metamorphic event during Permo-Triassic extension. Outer zircon rims with a late Cretaceous age (67.4 ± 1.9 Ma) are found only in the micaschist from Monte Mucrone. In metagabbro of the Ivozio Complex, zircon cores yield an intrusive age for the protolith of 340.7 ± 6.8 Ma, whereas Alpine allanite are dated at 62.9 ± 4.2 and 55.3 ± 7.3 Ma. The Cretaceous ages constrain the timing of the HP metamorphic stage. The presence of zircon overgrowth only in the central area of the Eclogite Micaschist Complex is attributed to local factors such as (1) multiple fluid pulses at HP that locally enhanced zircon dissolution and recrystallization, and (2) slightly higher temperatures reached in this area during HP metamorphism.
Force–displacement relations of bolted timber joints with slotted-in steel plates parallel to the grain
Authors: Liu Yingyang , Wang Yixuan , Zhang Yiming , Chen Minghui , Nie Xizhe
Published: December 2020

To study the force–displacement relations of bolted timber joints with slotted-in steel plates, we performed a monotonic loading test parallel to the grain on 24 specimens. The influences of the bolt diameter, timber thickness, and their ratio were considered. As shown by the test results, the joints had a high deformation capacity and experienced a linear stage, a stiffness degradation stage, a yield plateau stage, and a failure stage during loading. Based on the curve fitting and parameter identification, the force–displacement relations of the joints were summarized in a mechanical model with two parameters, i.e., the bearing capacity and the elastic stiffness. Based on theoretical analysis, we proposed a theoretical calculation formula for the bearing capacity and elastic stiffness of the joints. Finally, we calculated the force–displacement relation curves of bolted timber joints with slotted-in steel plates using the mechanical model and the theoretical formula. The calculated curves fitted well with the experimental curves.
Concurrent brain structural and functional alterations in patients with migraine without aura: an fMRI study
Authors: Li Zhengjie , Zhou Jun , Lan Lei , Cheng Shirui , Sun Ruirui , Gong Qiyong , Wintermark Max , Zeng Fang , Liang Fanrong
Published: December 2020

Objectives

To explore the possible concurrent brain functional and structural alterations in patients with migraine without aura (MwoA) patients compared to healthy subjects (HS).

Methods

Seventy-two MwoA patients and forty-six HS were recruited. 3D-T1 and resting state fMRI data were collected during the interictal period for MwoA and HS. Voxel-based morphometry (VBM) for structure analysis and regional homogeneity (Reho) for fMRI analysis were applied. The VBM and Reho maps were overlapped to determine a possible brain region with concurrent functional and structural alteration in MwoA patients. Further analysis of resting state functional connectivity (FC) alteration was applied with this brain region as the seed.

Results

Compared with HS, MwoA patients showed decreased volume in the bilateral superior and inferior colliculus, periaqueductal gray matter (PAG), locus ceruleus, median raphe nuclei (MRN) and dorsal pons medulla junction. MwoA patients showed decreased Reho values in the middle occipital gyrus and inferior occipital gyrus, and increased Reho values in the MRN. Only a region in the MRN showed both structural and functional alteration in MwoA patients. Pearson correlation analysis showed that there was no association between volume or Reho values of the MRN and headache frequency, headache intensity, disease duration, self-rating anxiety scale or self-rating depression scale in MwoA patients. Resting state functional connectivity (FC) with the MRN as the seed showed that MwoA patients had increased FC between the MRN and PAG.

Conclusions

MRN are involved in the pathophysiology of migraine during the interictal period. This study may help to better understand the migraine symptoms.

Trial registration

NCT01152632. Registered 27 June 2010.