bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of ustekinumab in biologic-naïve patients with psoriatic arthritis by prior treatment exposure and disease duration: data from PSUMMIT 1 and PSUMMIT 2
Authors: McInnes Iain B , Chakravarty Soumya D , Apaolaza Isabel , Kafka Shelly , Hsia Elizabeth C , You Yin , Kavanaugh Arthur 
Published: August 2019

ObjectiveTo evaluate the efficacy of ustekinumab by prior treatment exposure and disease duration in tumour necrosis factor inhibitor (TNF)-naïve patients with psoriatic arthritis (PsA) in the PSUMMIT 1 and PSUMMIT 2 studies.MethodsIn the phase 3, randomised, placebo-controlled PSUMMIT 1 and PSUMMIT 2 studies, adults with active PsA for ≥6 months despite conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or non-steroidal anti-inflammatory drugs (NSAIDs) (PSUMMIT 1) or csDMARDs, NSAIDs and/or anti-TNF agents (PSUMMIT 2) were enrolled. Patients were randomised to subcutaneous injections of placebo, ustekinumab 45 mg or ustekinumab 90 mg at weeks 0 and 4 and every 12 weeks. Efficacy was assessed at week 24 using the American College of Rheumatology criteria and 28-joint count disease activity score using C reactive protein (DAS28-CRP); radiographical progression, enthesitis, and dactylitis were also assessed in this post hoc analysis.ResultsA total of 747 patients were included; all 747 were TNF-naïve, of which, 179 were methotrexate-naïve and TNF-naïve, and 146 were all csDMARD-naïve and TNF-naïve. At week 24, greater proportions of ustekinumab-treated patients had ≥20%/50%/70% improvement in American College of Rheumatology criteria (ACR20/ACR50/ACR70) responses, DAS28-CRP response and DAS28-CRP remission versus placebo in all three prior-treatment populations, with similar differences between treatment groups. Greater proportions of ustekinumab-treated patients also had complete resolution of enthesitis and dactylitis at week 24 across the three prior-treatment populations. Mean changes from baseline in total van der Heijde-Sharp Score at week 24 were generally smaller for ustekinumab-treated patients versus placebo but were statistically significant only in the full TNF-naïve population. Response rates for ACR20/ACR50/ACR70 were similar for TNF-naïve patients with PsA durations of <1 year, ≥1 to <3 years, and ≥3 years.ConclusionUstekinumab-treated patients demonstrated greater clinical response at week 24 compared with placebo regardless of prior treatment exposure and PsA disease duration.
Research on reflective three-output by packaged grating under second Bragg angle
Authors: Zhu Wenhua , Wang Bo , Gao Chenhao , Wen Kunhua , Meng Ziming , Nie Zhaogang , Wang Qu , Xing Xiangjun , Chen Li , Lei Liang , Zhou Jinyun 
Published: August 2019

This paper designed a novel three-output reflective packaged grating. The optimized parameters such as the period and depth of the high-efficiency three-output grating with an incident wavelength of 1550 nm can be calculated by rigorous coupled-wave analysis (RCWA). According to the optimized result, the grating can diffract the incident light energy into three orders with an efficiency of nearly 33% under the premise of second Bragg angle incidence and the given duty ratio of 0.5. The diffraction efficiency of the packaged grating is improved compared to the surface-relief three-output grating under second Bragg angle incidence, especially for TE-polarized light.
Establishing the Impact of Vascular Damage on Tumor Response to High-Dose Radiation Therapy
Authors: Castle Katherine D. , Kirsch David G. 
Published: August 2019

Abstract
Approximately half of all patients with cancer receive radiotherapy, which is conventionally delivered in relatively small doses (1.8–2 Gy) per daily fraction over one to two months. Stereotactic body radiation therapy (SBRT), in which a high daily radiation dose is delivered in 1 to 5 fractions, has improved local control rates for several cancers. However, despite the widespread adoption of SBRT in the clinic, controversy surrounds the mechanism by which SBRT enhances local control. Some studies suggest that high doses of radiation (≥10 Gy) trigger tumor endothelial cell death, resulting in indirect killing of tumor cells through nutrient depletion. On the other hand, mathematical models predict that the high radiation dose per fraction used in SBRT increases direct tumor cell killing, suggesting that disruption of the tumor vasculature is not a critical mediator of tumor cure. Here, we review the application of genetically engineered mouse models to radiosensitize tumor cells or endothelial cells to dissect the role of these cellular targets in mediating the response of primary tumors to high-dose radiotherapy in vivo. These studies demonstrate a role for endothelial cell death in mediating tumor growth delay, but not local control following SBRT.
First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma
Authors: Allen Bryan G. , Bodeker Kellie L. , Smith Mark C. , Monga Varun , Sandhu Sonia , Hohl Raymond , Carlisle Thomas , Brown Heather , Hollenbeck Nancy , Vollstedt Sandy , Greenlee Jeremy D. , Howard Matthew A. , Mapuskar Kranti A. , Seyedin Steven N. , Caster Joseph M. , Jones Karra A. , Cullen Joseph J. , Berg Daniel , Wagner Brett A. , Buettner Garry R. , TenNapel Mindi J. , Smith Brian J. , Spitz Douglas R. , Buatti John M. 
Published: August 2019

Abstract

Purpose:
Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH−) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH− to standard RT/TMZ therapy.

Patients and Methods:
This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH−) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH− phase). Eight P-AscH− dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH− doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH− was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03).

Results:
Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n = 8), median PFS was 10 months and median OS was 23 months.

Conclusions:
P-AscH−/RT/TMZ is safe with promising clinical outcomes warranting further investigation.
Late Gadolinium Enhancement Magnetic Resonance Imaging Guided Treatment of Post–Atrial Fibrillation Ablation Recurrent Arrhythmia
Authors: Fochler Franziska , Yamaguchi Takanori , Kheirkahan Mobin , Kholmovski Eugene G. , Morris Alan K. , Marrouche Nassir F. 
Published: August 2019

Background:
Macroreentrant atrial tachycardia (AT) accounts for 40% to 60% of recurrent atrial arrhythmias after atrial fibrillation (AF) ablation. To describe late gadolinium enhancement magnetic resonance imaging (LGE-MRI)–detected scar-based dechanneling as new ablation strategy to treat ATs after AF ablation.

Methods:
Data from 102 patients who underwent initial AF ablation and repeat ablation for recurrent atrial arrhythmia within 1-year follow-up were analyzed. All patients underwent LGE-MRI before initial and repeat ablation. Depending on the recurrent rhythm, patients with AF and AT recurrence were assigned to group 1 or 2, respectively. Group 1 underwent fibrosis homogenization as second procedure. Group 2 underwent LGE-MRI–detected scar-based dechanneling. Both groups underwent reisolation of pulmonary veins if necessary.

Results:

Forty-six patients (45%) presented with AF, and 56 patients (55%) presented with AT recurrence during follow-up after initial ablation. In the first 25 patients from group 2, the AT was electroanatomically mapped, and a critical isthmus was defined. It was found that those isthmi were located in the regions with nontransmural scarring detected by LGE-MRI. In the last 31 patients from group 2, an empirical LGE-MRI–based dechanneling was performed solely based on the LGE-MRI results. During 1-year follow-up after second ablation, 67% patients in group 1 and 64% patients in group 2 were free from recurrence (log-rank,
P
=1.000). In group 2, 64% in the electroanatomically guided and 65% in the LGE-MRI dechanneling group were free from recurrence (log-rank,
P
=0.900).

Conclusions:
Anatomic targeting of LGE-MRI–detected gaps and superficial atrial scar is feasible and effective to treat recurrent arrhythmias post-AF ablation. Homogenization of existing scar is the appropriate treatment for recurrent AF, whereas dechanneling of existing isthmi seems the right approach for patients recurring with AT.
Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease
Authors: Agha Golareh , Mendelson Michael M. , Ward-Caviness Cavin K. , Joehanes Roby , Huan TianXiao , Gondalia Rahul , Salfati Elias , Brody Jennifer A. , Fiorito Giovanni , Bressler Jan , Chen Brian H. , Ligthart Symen , Guarrera Simonetta , Colicino Elena , Just Allan C. , Wahl Simone , Gieger Christian , Vandiver Amy R. , Tanaka Toshiko , Hernandez Dena G. , Pilling Luke C. , Singleton Andrew B. , Sacerdote Carlotta , Krogh Vittorio , Panico Salvatore , Tumino Rosario , Li Yun , Zhang Guosheng , Stewart James D. , Floyd James S. , Wiggins Kerri L. , Rotter Jerome I. , Multhaup Michael , Bakulski Kelly , Horvath Steven , Tsao Philip S. , Absher Devin M. , Vokonas Pantel , Hirschhorn Joel , Fallin M. Daniele , Liu Chunyu , Bandinelli Stefania , Boerwinkle Eric , Dehghan Abbas , Schwartz Joel D. , Psaty Bruce M. , Feinberg Andrew P. , Hou Lifang , Ferrucci Luigi , Sotoodehnia Nona , Matullo Giuseppe , Peters Annette , Fornage Myriam , Assimes Themistocles L. , Whitsel Eric A. , Levy Daniel , Baccarelli Andrea A. 
Published: August 2019

Background:
DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

Methods:
Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

Results:
Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

Conclusion:
Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
Systemic Inflammation Rapidly Induces Reversible Atrial Electrical Remodeling: The Role of Interleukin‐6–Mediated Changes in Connexin Expression
Authors: Lazzerini Pietro Enea , Laghi‐Pasini Franco , Acampa Maurizio , Srivastava Ujala , Bertolozzi Iacopo , Giabbani Beatrice , Finizola Francesco , Vanni Francesca , Dokollari Aleksander , Natale Mariarita , Cevenini Gabriele , Selvi Enrico , Migliacci Nicola , Maccherini Massimo , Boutjdir Mohamed , Capecchi Pier Leopoldo 
Published: August 2019

Background
Systemic inflammation is a strong predictor of atrial fibrillation. A key role for electrical remodeling is increasingly recognized, and experimental data suggest that inflammatory cytokines can directly affect connexins resulting in gap‐junction dysfunction. We hypothesized that systemic inflammation, regardless of its origin, promotes atrial electric remodeling in vivo, as a result of cytokine‐mediated changes in connexin expression.

Methods and Results
Fifty‐four patients with different inflammatory diseases and elevated C‐reactive protein were prospectively enrolled, and electrocardiographic P‐wave dispersion indices, cytokine levels (interleukin‐6, tumor necrosis factor‐α, interleukin‐1, interleukin‐10), and connexin expression (connexin 40, connexin 43) were measured during active disease and after reducing C‐reactive protein by >75%. Moreover, peripheral blood mononuclear cells and atrial tissue specimens from an additional sample of 12 patients undergoing cardiac surgery were evaluated for atrial and circulating mRNA levels of connexins. Finally, in vitro effects of interleukin‐6 on connexin expression were studied in HL‐1 mouse atrial myocytes. In patients with active inflammatory diseases, P‐wave dispersion indices were increased but rapidly decreased within days when C‐reactive protein normalizes and interleukin‐6 levels decline. In inflammatory disease patients, both P‐wave dispersion indices and interleukin‐6 changes were inversely associated with circulating connexin levels, and a positive correlation between connexin expression in peripheral blood mononuclear cells and atrial tissue was demonstrated. Moreover, interleukin‐6 significantly reduced connexin expression in HL‐1 cells.

Conclusions
Our data suggest that regardless of specific etiology and organ localization, systemic inflammation, via interleukin‐6 elevation, rapidly induces atrial electrical remodeling by down‐regulating cardiac connexins. Although transient, these changes may significantly increase the risk for atrial fibrillation and related complications during active inflammatory processes.
Effect of Baseline Kidney Function on the Risk of Recurrent Stroke and on Effects of Intensive Blood Pressure Control in Patients With Previous Lacunar Stroke: A Post Hoc Analysis of the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes)
Authors: Agarwal Adhish , Cheung Alfred K. , Ma Jianing , Cho Monique , Li Man 
Published: August 2019

Background

We conducted a post hoc analysis of the SPS3 (Secondary Prevention of Small Subcortical Strokes) Trial to examine the association of chronic kidney disease (
CKD
) with
recurrent
stroke, and to assess whether baseline renal function modifies the effects of intensive systolic blood pressure control in patients with previous stroke.

Methods and Results

A total of 3020 patients with recent magnetic resonance imaging–defined symptomatic lacunar infarctions were randomized to a systolic blood pressure target of <130 mm Hg versus 130 to 149 mm Hg. Predefined primary outcomes were (all‐recurrent) stroke and a composite of stroke, acute myocardial infarction, or all‐cause death; secondary outcomes were acute myocardial infarction, all‐cause death, and intracerebral hemorrhage individually. Among 3017 patients with baseline estimated glomerular filtration rate measurements, we evaluated, using Cox proportional hazards models, the association of
CKD
with recurrent stroke and effects of the blood pressure targets on outcomes using baseline estimated glomerular filtration rate both as a categorical and linear variable. Regardless of the randomized treatment,
CKD
at baseline was significantly associated with an increased risk of the primary cardiovascular composite outcome (hazard ratio, 1.7; 95% CI, 1.4–2.1), and all‐recurrent stroke (1.5; 1.1–2.0). However, the effects of the lower systolic blood pressure intervention on the primary outcome were not influenced by baseline
CKD
status (
P
for interaction=0.62).

Conclusions

CKD
increases the risk of recurrent stroke by 50% in patients with previous lacunar stroke. We found no definitive evidence that renal dysfunction modifies the effects of systolic blood pressure control in patients with previous stroke. Conclusive evidence for this will require adequately powered studies with moderate‐to‐advanced
CKD
.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
00059306.
Systematic Review of Malpractice Litigation in the Diagnosis and Treatment of Acute Stroke
Authors: Haslett Jack J. , Genadry Lisa , Zhang Xiangnan , LaBelle Lindsey A. , Bederson Joshua , Mocco J , Kellner Christopher P. 
Published: August 2019

Background and Purpose—
The emergency management of stroke is complex and highly time-sensitive. Recent landmark trials demonstrating the strong benefit of thrombectomy have led to rapid change in stroke management. This article reviews a large number of medical malpractice lawsuits related to the emergency management of stroke to characterize factors involved in these lawsuits.

Methods—
Three large legal databases were used to search for jury verdicts and settlements in cases related to the acute care of stroke patients in the United States. Search terms included “stroke” and “medical malpractice.” Cases were screened to include only cases in which the allegation involved negligence in the acute care of a patient suffering a stroke.

Results—
We found 246 medical malpractice cases related to the acute management of ischemic stroke and 26 related to intracranial hemorrhage. Seventy-one cases specifically alleged a failure to treat with tPA (tissue-type plasminogen activator) and 7 cases alleged a failure to treat, or to timely treat, with thrombectomy. Overall there were 151 cases (56%) which ended with no payout, 74 cases (27%) were settled out of court, and 47 cases (17%) went to court and resulted in a verdict for the plaintiff. The average payout in settlements was $1 802 693, and the average payout in plaintiff verdicts was $9 705 099.

Conclusions—
Malpractice litigation is a risk in acute stroke care and can lead to significant financial consequences. The majority of malpractice lawsuits related to the emergency management of stroke allege a failure to diagnose and failure to treat. Allegations of a failure to treat acute ischemic stroke with tPA were frequently found and are common in lawsuits. Allegations of a failure to treat a large vessel occlusion with thrombectomy were less frequently found. Given recent changes in practice guidelines and the demonstrated strong treatment effect of thrombectomy, it is likely that such litigation will increase in the coming years.
Non–Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Asians With Atrial Fibrillation
Authors: Xue Zhengbiao , Zhang Hao 
Published: August 2019

Background and Purpose—
Several randomized trials and real-world studies have reported the efficacy and safety of non–vitamin K antagonist oral anticoagulants (NOACs) in Asian patients with atrial fibrillation; and therefore, this meta-analysis was aimed to compare the effects of NOACs with warfarin for atrial fibrillation stroke prevention in Asians.

Methods—
The PubMed and Embase databases were searched from January 2009 to February 2019 for studies on comparisons of NOACs versus warfarin in Asians. Risk ratios (RRs) with 95% CIs were pooled using a random-effects model.

Results—
Five NOAC trials and 21 observational cohorts were included. For the NOAC trials, compared with warfarin, NOACs was associated with reduced risks of stroke or systemic embolism (RR, 0.73; 95% CI, 0.59–0.90), all-cause death (RR, 0.83; 95% CI, 0.73–0.95), major bleeding (RR, 0.59; 95% CI, 0.48–0.72), and intracranial bleeding (RR, 0.36; 95% CI, 0.26–0.49). For the real-world data, compared with warfarin, NOACs was associated with decreased rates of stroke or systemic embolism (RR, 0.75; 95% CI, 0.68–0.82), ischemic stroke (RR, 0.70; 95% CI, 0.59–0.83), myocardial infarction (RR, 0.74; 95% CI, 0.58–0.93), all-cause death (RR, 0.67; 95% CI, 0.59–0.77), major bleeding (RR, 0.63; 95% CI, 0.55–0.73), intracranial bleeding (RR, 0.50; 95% CI, 0.43–0.59), and gastrointestinal bleeding (RR, 0.65; 95% CI, 0.51–0.84). The results did not change in the subgroup analyses based on the type and dose of NOACs.

Conclusions—
Based on published NOAC trials and real-world studies, the use of NOACs is noninferior to warfarin in Asians with atrial fibrillation irrespective of the NOAC type and dose.
Mode-Decomposed Equation Diagnosis for Atmospheric Blocking Development
Authors: Aikawa Takuya , Inatsu Masaru , Nakano Naoto , Iwano Tetsuya 
Published: August 2019

AbstractThis paper proposes a new method to identify atmospheric blocking development without the time filtering used in previous studies. A mode-decomposed vorticity equation is formulated from the principal components (PCs) of 500-hPa geopotential height by applying a new idea; the orthonormality of PCs allows any variable to be decomposed into a projection corresponding to the PCs. To test this, sectorial blocking episodes in Northern Hemisphere winter were identified by Barriopedro’s method. A blocking index was defined for each longitudinal range as the linear combination of the 10 largest PCs by means of the composite for the blocking episodes. Blocking development was diagnosed, in terms of the low modes of PC1–PC10 and the high modes of PC11–PC50. The results suggest that the intensification of blocking over the North Pacific and Eurasia is associated with nonlinear interaction among high modes, whereas the intensification (decay) of North Atlantic blocks is related mainly to enhanced nonlinear interaction among low-frequency (high-frequency) eddies. This main result is insensitive to the choice of definition for blocks and the choice of the mode separation boundary.
Impact of Vertical Wind Shear on Gravity Wave Propagation in the Land–Sea-Breeze Circulation at the Equator
Authors: Du Yu , Rotunno Richard , Zhang Fuqing 
Published: August 2019

Abstract
The impact of vertical wind shear on the land–sea-breeze circulation at the equator is explored using idealized 2D numerical simulations and a simple 2D linear analytical model. Both the idealized and linear analytical models indicate Doppler shifting and attenuation effects coexist under the effect of vertical wind shear for the propagation of gravity waves that characterize the land–sea-breeze circulation. Without a background wind, the idealized sea breeze has two ray paths of gravity waves that extend outward and upward from the coast. A uniform background wind causes a tilting of the two ray paths due to Doppler shifting. With vertical shear in the background wind, the downstream ray path of wave propagation can be rapidly attenuated near a certain level, whereas the upstream ray path is not attenuated and the amplitudes even increase with height. The downstream attenuation level is found to descend with increasing linear wind shear. The present analytical model establishes that the attenuation level corresponds to the critical level where the background wind is equal to the horizontal gravity wave phase speed. The upstream gravity wave ray path can propagate upward without attenuation as there is no critical level there.