bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells
Authors: Dovedi Simon J. , Elder Matthew J. , Yang Chunning , Sitnikova Suzanne I. , Irving Lorraine , Hansen Anna , Hair James , Jones Des C. , Hasani Sumati , Wang Bo , Im Seock-Ah , Tran Ben , Subramaniam Deepa S. , Gainer Shelby D. , Vashisht Kapil , Lewis Arthur , Jin Xiaofang , Kentner Stacy , Mulgrew Kathy , Wang Yaya , Overstreet Michael G. , Dodgson James , Wu Yanli , Palazon Asis , Morrow Michelle , Rainey Godfrey J. , Browne Gareth J. , Neal Frances , Murray Thomas V. , Toloczko Aleksandra D. , Dall'Acqua William , Achour Ikbel , Freeman Daniel J. , Wilkinson Robert W. , Mazor Yariv 
Published: January 2021

Abstract

The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1− T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells.

Significance:
The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy.
See related commentary by Burton and Tawbi, p. 1008.
This article is highlighted in the In This Issue feature, p. 995
Periaortic Ventricular Tachycardias in Nonischemic Cardiomyopathy
Authors: Nakajima Ikutaro , Narui Ryohsuke , Aboud Asad A. , Adeola Oluwaseun , McHugh Julia , Holmes Benjamin , Lugo Ricardo , Richardson Travis D. , Montgomery Jay , Shen Sharon , Kanagasundram Arvindh , Michaud Gregory F. , Stevenson William G. 
Published: January 2021

Background:
Periaortic fibrotic ventricular tachycardia (VT) substrate is common in nonischemic cardiomyopathy (NICM), often intramural, and difficult to ablate. We sought to better characterize normal and abnormal periaortic voltage map parameters and NICM periaortic VTs.

Methods:
In 15 patients without heart disease, the 5th percentile of endocardial voltage for increasing distance from the aortic valve ring was determined. In 53 consecutive patients with NICM (64±11 years; left ventricular ejection fraction 31±10%) undergoing ablation of recurrent VT, periaortic electrogram voltage and VT characteristics were analyzed.

Results:

In healthy patients, the fifth percentile of the bipolar voltage increased proportional to the distance from the aortic valve ring, from 1.0 mV at 1 cm to 1.5 mV at 1.5 cm; the corresponding unipolar voltage cutoffs were 5.0 and 7.5 mV. A total of 160 VTs were induced in 53 patients with NICM, of which 28 VTs in 20 patients had periaortic origins. Periaortic VTs were associated with similar periaortic bipolar voltage, but lower UVs consistent with intramural fibrosis as an important substrate. Periaortic VTs could be divided into left and right bundle branch block forms with mapping showing right septal and lateral exits. Left bundle branch block VTs were more often acutely abolished with ablation (100% versus 69%;
P
=0.034), but with a 23% incidence of heart block. Greater extent of low voltage was associated with more induced VTs and worse acute outcome.

Conclusions:
Adjusting voltage parameters based on distance from the aortic valve may improve definition of left ventricular outflow tract arrhythmia substrate. Periaortic VTs are common in NICM, often associated with intramural substrate and can be divided into left bundle branch block and right bundle branch block types associated with different ablation outcomes and risks.
Cryoballoon Versus Laserballoon
Authors: Chun Julian K.R. , Bordignon Stefano , Last Jana , Mayer Lukas , Tohoku Shota , Zanchi Simone , Bianchini Lorenzo , Bologna Fabrizio , Nagase Takahiko , Urbanek Lukas , Chen Shaojie , Schmidt Boris 
Published: January 2021

Background:
Pulmonary vein isolation (PVI) represents the cornerstone in atrial fibrillation ablation. Cryoballoon and laserballoon catheters have emerged as promising devices but lack randomized comparisons. Therefore, we sought to compare efficacy and safety comparing both balloons in patients with persistent and paroxysmal atrial fibrillation (AF).

Methods:
Symptomatic AF patients (n=200) were prospectively randomized (1:1) to receive either cryoballoon or laserballoon PVI (cryoballoon: n=100: 50 paroxysmal atrial fibrillation + 50 persistent AF versus laserballoon: n=100: 50 paroxysmal atrial fibrillation + 50 persistent AF). All antiarrhythmic drugs were stopped after ablation. Follow-up included 3-day Holter-ECG recordings and office visits at 3, 6, and 12 months. Primary efficacy end point was defined as freedom from atrial tachyarrhythmia between 90 and 365 days after a single ablation. Secondary end points included procedural parameters and periprocedural complications.

Results:

Patient baseline parameters were not different between both groups. In all (n=200) complete PVI was obtained and the entire follow-up accomplished. Balloon only PVI was obtained in 98% (cryoballoon) versus 95% (laserballoon) requiring focal touch-up in 2 and 5 patients, respectively. Procedure but not fluoroscopy time was significantly shorter in the cryoballoon group (50.9±21.0 versus 96.0±20.4 minutes;
P
<0.0001 and 7.4±4.4 versus 8.4±3.2 minutes,
P
=0.083). Overall, the primary end point of no atrial tachyarrhythmia recurrence was met in 79% (cryoballoon: 80.0% versus laserballoon: 78.0%,
P
=ns). No death, atrio-esophageal fistula, tamponade, or vascular laceration requiring surgery occurred. In the cryoballoon group, 8 transient but no persistent phrenic nerve palsy were noted compared with 2 persistent phrenic nerve palsy and one transient ischemic attack in the laserballoon group.

Conclusions:
Both balloon technologies represent highly effective and safe tools for PVI resulting in similar favorable rhythm outcome after 12 months. Use of the cryoballoon is associated with significantly shorter procedure but not fluoroscopy time.
Transition From an Open to Closed Staffing Model in the Cardiac Intensive Care Unit Improves Clinical Outcomes
Authors: Miller P. Elliott , Chouairi Fouad , Thomas Alexander , Kunitomo Yukiko , Aslam Faisal , Canavan Maureen E. , Murphy Christa , Daggula Krishna , Metkus Thomas , Vallabhajosyula Saraschandra , Carnicelli Anthony , Katz Jason N. , Desai Nihar R. , Ahmad Tariq , Velazquez Eric J. , Brennan Joseph 
Published: January 2021

Background
Several studies have shown improved outcomes in closed compared with open medical and surgical intensive care units. However, very little is known about the ideal organizational structure in the modern cardiac intensive care unit (CICU).

Methods and Results

We retrospectively reviewed consecutive unique admissions (n=3996) to our tertiary care CICU from September 2013 to October 2017. The aim of our study was to assess for differences in clinical outcomes between an open compared with a closed CICU. We used multivariable logistic regression adjusting for demographics, comorbidities, and severity of illness. The primary outcome was in‐hospital mortality. We identified 2226 patients in the open unit and 1770 in the closed CICU. The unadjusted in‐hospital mortality in the open compared with closed unit was 9.6% and 8.9%, respectively (
P
=0.42). After multivariable adjustment, admission to the closed unit was associated with a lower in‐hospital mortality (odds ratio [OR], 0.69; 95% CI: 0.53–0.90,
P
=0.007) and CICU mortality (OR, 0.70; 95% CI, 0.52–0.94,
P
=0.02). In subgroup analysis, admissions for cardiac arrest (OR, 0.42; 95% CI, 0.20–0.88,
P
=0.02) and respiratory insufficiency (OR, 0.43; 95% CI, 0.22–0.82,
P
=0.01) were also associated with a lower in‐hospital mortality in the closed unit. We did not find a difference in CICU length of stay or total hospital charges (
P
>0.05).

Conclusions
We found an association between lower in‐hospital and CICU mortality after the transition to a closed CICU. These results may help guide the ongoing redesign in other tertiary care CICUs.
Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Prior Gastrointestinal Bleeding
Authors: Kwon Soonil , Lee So-Ryoung , Choi Eue-Keun , Lee Euijae , Jung Jin-Hyung , Han Kyung-Do , Cha Myung-Jin , Oh Seil , Lip Gregory Y.H. 
Published: January 2021

Background and Purpose:
Limited data support the benefits of non–vitamin K oral anticoagulants (NOACs) among atrial fibrillation patients with prior gastrointestinal bleeding (GIB). We aimed to evaluate the effectiveness and safety of NOACs compared with those of warfarin among atrial fibrillation patients with prior GIB.

Methods:
Oral anticoagulant–naive individuals with atrial fibrillation and prior GIB between January 2010 and April 2018 were identified from the Korean claims database. NOAC users were compared with warfarin users by balancing covariates using the inverse probability of treatment weighting method. The primary outcomes were ischemic stroke, major bleeding, and the composite outcome (combined ischemic stroke and major bleeding). Fatal events from each outcome were evaluated as secondary outcomes.

Results:

A total of 42 048 patients were included (24 781 in the NOAC group and 17 267 in the warfarin group). The mean time from prior GIB to the initiation of oral anticoagulant was 3.1±2.6 years. After inverse probability of treatment weighting, baseline characteristics were balanced between the two groups (mean age, 72 years; men, 56.8%; and mean CHA
2
DS
2
-VASc score, 3.7). Lower risks of ischemic stroke, major bleeding, and the composite outcome were associated with NOAC use than with warfarin use (weighted hazard ratio, 0.608 [95% CI, 0.543–0.680]; hazard ratio, 0.731 [95% CI, 0.642–0.832]; and hazard ratio, 0.661 [95% CI, 0.606–0.721], respectively). For all secondary outcomes, NOACs showed greater risk reductions compared with warfarin.

Conclusions:
NOACs were associated with lower risks of ischemic stroke and major bleeding than warfarin among atrial fibrillation patients with prior GIB.
Unique Subtype of Microglia in Degenerative Thalamus After Cortical Stroke
Authors: Cao Zhijuan , Harvey Sean S. , Chiang Terrance , Foltz Aulden G. , Lee Alex G. , Cheng Michelle Y. , Steinberg Gary K. 
Published: January 2021

Background and Purpose:
Stroke disrupts neuronal functions in both local and remotely connected regions, leading to network-wide deficits that can hinder recovery. The thalamus is particularly affected, with progressive development of neurodegeneration accompanied by inflammatory responses. However, the complexity of the involved inflammatory responses is poorly understood. Herein we investigated the spatiotemporal changes in the secondary degenerative thalamus after cortical stroke, using targeted transcriptome approach in conjunction with histology and flow cytometry.

Methods:

Cortical ischemic stroke was generated by permanent occlusion of the left middle cerebral artery in male C57BL6J mice. Neurodegeneration, neuroinflammatory responses, and microglial activation were examined in naive and stroke mice at from poststroke days (PD) 1 to 84, in both ipsilesional somatosensory cortex and ipsilesional thalamus. NanoString neuropathology panel (780 genes) was used to examine transcriptome changes at PD7 and PD28. Fluorescence activated cell sorting was used to collect CD11c
+
microglia from ipsilesional thalamus, and gene expressions were validated by quantitative real-time polymerase chain reaction.

Results:

Neurodegeneration in the thalamus was detected at PD7 and progressively worsened by PD28. This was accompanied by rapid microglial activation detected as early as PD1, which preceded the neurodegenerative changes. Transcriptome analysis showed higher number of differentially expressed genes in ipsilesional thalamus at PD28. Notably, neuroinflammation was the top activated pathway, and microglia was the most enriched cell type.
Itgax
(CD11c) was the most significantly increased gene, and its expression was highly detected in microglia. Flow-sorted CD11c
+
microglia from degenerative thalamus indicated molecular signatures similar to neurodegenerative disease–associated microglia; these included downregulated Tmem119 and CX3CR1 and upregulated ApoE, Axl, LpL, CSF1, and Cst7.

Conclusions:

Our findings demonstrate the dynamic changes of microglia after stroke and highlight the importance of investigating stroke network-wide deficits. Importantly, we report the existence of a unique subtype of microglia (CD11c
+
) with neurodegenerative disease–associated microglia features in the degenerative thalamus after stroke.
Atypical core-periphery brain dynamics in autism
Authors: Roy Dipanjan , Uddin Lucina Q. 
Published: January 2021

Abstract
The intrinsic function of the human brain is dynamic, giving rise to numerous behavioral subtypes that fluctuate distinctively at multiple timescales. One of the key dynamical processes that takes place in the brain is the interaction between core-periphery brain regions, which undergoes constant fluctuations associated with developmental time frames. Core-periphery dynamical changes associated with macroscale brain network dynamics span multiple timescales and may lead to atypical behavior and clinical symptoms. For example, recent evidence suggests that brain regions with shorter intrinsic timescales are located at the periphery of brain networks (e.g., sensorimotor hand, face areas) and are implicated in perception and movement. On the contrary, brain regions with longer timescales are core hub regions. These hubs are important for regulating interactions between the brain and the body during self-related cognition and emotion. In this review, we summarize a large body of converging evidence derived from time-resolved fMRI studies in autism to characterize atypical core-periphery brain dynamics and how they relate to core and contextual sensory and cognitive profiles.
The Pirate and the Admiral: Europeanisation and Globalisation of Maritime Conflict Management
Authors: Sicking Louis 
Published: January 2021

AbstractPiracy holds a special place within the field of international law because of the universal jurisdiction that applies: any state may seize a pirate ship on the high seas and decide upon the penalties to be imposed, as is currently the case with Somali and West African pirates. Unlike today, piracy was the norm in pre-modern times. Maritime trade and piracy went hand in hand. At the same time, kings and emperors recruited their admirals from among pirates. This raises the question of how princes, states and cities distinguished between legal and illegal violence at sea. How did they deal with maritime conflict among themselves and among their respective subjects and citizens? This article puts maritime conflict management in a European, global and long term perspective while avoiding anachronistic and teleological approaches. Finally, it argues that pre-modern conflict management is relevant to understand maritime security in the twenty-first century.
Children sharing Preferences on Contact and Residence Arrangements in Child-inclusive Family Mediation in Norway
Authors: Grape Lovise , Thørnblad Renee , Handegård Bjørn Helge 
Published: January 2021

Abstract
Mediation is mandatory for all separating and divorcing parents in Norway with children under 16 years. The participation of children is voluntary. Living arrangement preferences presented by children attending child-inclusive family mediation in Norway (n = 346, aged 4–18 years) have been examined. 47.1 per cent of children gave a living arrangement preference, and older children were more likely to express a preference for living primarily with the mother compared to an equal time-sharing arrangement. Children very often gave reasoned explanations for their wishes. Children’s utilisation of the potential in their participation supports future inclusion of children in mediation processes. The best interests of the child needs to be examined on an individual basis as children present various preferences that is not in line with a presumption of fixed time-sharing following parental break-up.
Evaluation of the Surface Wind Field over Land in WRF Simulations of Hurricane Wilma (2005). Part I: Model Initialization and Simulation Validation
Authors: Nolan David S. , McNoldy Brian D. , Yunge Jimmy 
Published: January 2021

AbstractAlthough global and regional dynamical models are used to predict the tracks and intensities of hurricanes over the ocean, these models are not currently used to predict the wind field and other impacts over land. This two-part study performs detailed evaluations of the near-surface, overland wind fields produced in simulations of Hurricane Wilma (2005) as it traveled across South Florida. This first part describes the production of two high-resolution simulations using the Weather Research and Forecasting (WRF) Model, using different boundary layer parameterizations available in WRF: the Mellor–Yamada–Janjić (MYJ) scheme and the Yonsei University (YSU) scheme. Initial conditions from the Global Forecasting System are manipulated with a vortex-bogusing technique to modify the initial intensity, size, and location of the cyclone. It is found possible through trial and error to successfully produce simulations using both the YSU and MYJ schemes that closely reproduce the track, intensity, and size of Wilma at landfall. For both schemes the storm size and structure also show good agreement with the wind fields diagnosed by H*WIND and the Tropical Cyclone Surface Wind Analysis. Both over water and over land, the YSU scheme has stronger winds over larger areas than does the MYJ, but the surface winds are more reduced in areas of greater surface roughness, particularly in urban areas. Both schemes produced very similar inflow angles over land and water. The overland wind fields are examined in more detail in the second part of this study.
Evaluation of the Surface Wind Field over Land in WRF Simulations of Hurricane Wilma (2005). Part II: Surface Winds, Inflow Angles, and Boundary Layer Profiles
Authors: Nolan David S. , McNoldy Brian D. , Yunge Jimmy , Masters Forrest J. , Giammanco Ian M. 
Published: January 2021

AbstractThis is the second of a two-part study that explores the capabilities of a mesoscale atmospheric model to reproduce the near-surface wind fields in hurricanes over land. The Weather Research and Forecasting (WRF) Model is used with two planetary boundary layer parameterizations: the Yonsei University (YSU) and the Mellor–Yamada–Janjić (MYJ) schemes. The first part presented the modeling framework and initial conditions used to produce simulations of Hurricane Wilma (2005) that closely reproduced the track, intensity, and size of its wind field as it passed over South Florida. This part explores how well these simulations can reproduce the winds at fixed points over land by making comparisons with observations from airports and research weather stations. The results show that peak wind speeds are remarkably well reproduced at several locations. Wind directions are evaluated in terms of the inflow angle relative to the storm center, and the simulated inflow angles are generally smaller than observed. Localized peak wind events are associated with vertical vorticity maxima in the boundary layer with horizontal scales of 5–10 km. The boundary layer winds are compared with wind profiles obtained by velocity–azimuth display (VAD) analyses from National Weather Service Doppler radars at Miami and Key West, Florida; results from these comparisons are mixed. Nonetheless the comparisons with surface observations suggest that when short-term hurricane forecasts can sufficiently predict storm track, intensity, and size, they will also be able to provide useful information on extreme winds at locations of interest.
Longitudinal effect of disease-modifying therapy on tricuspid regurgitant velocity in children with sickle cell anemia
Authors: Rai Parul , Joshi Vijaya M. , Goldberg Jason F. , Yates Amber M. , Okhomina Victoria I. , Penkert Rhiannon , Ataga Kenneth I. , Kang Guolian , Hankins Jane S. 
Published: January 2021

AbstractElevated tricuspid regurgitant velocity (TRV) ≥2.5 m/s is a predictor of disease severity in adults and children with sickle cell anemia (SCA), but how disease-modifying therapies (DMTs) affect this biomarker is incompletely understood. We investigated the effect of DMTs on TRV elevation in children. In a prospective single-center study, 204 subjects with HbSS or HbSβ0 thalassemia (mean age, 10.6 years; range, 5-18) had echocardiograms with assessment of TRV, with repeat evaluations after 2 years of observation. One-hundred and twelve participants received DMTs (hydroxyurea, n = 72; monthly erythrocyte transfusions, n = 40), 58 did not receive any DMT, and 34 were begun on hydroxyurea during this observation period. In the entire cohort, an increase in hemoglobin of 1.0 g/dL was associated with a 0.03-m/s decrease in TRV (P = .024), and a decrease in absolute reticulocyte count of 1.0 × 106/mL was associated with a 0.34-m/s decrease in TRV (P = .034). Compared with baseline, hydroxyurea exposure (continuous or newly started) was associated with an average 5% decline in mean TRV at the 2-year evaluation. Among participants newly started on hydroxyurea (mean treatment duration 1.2 ± 0.6 years), an increase in hemoglobin of 1.0 g/dL was associated with a 0.06-m/s decrease in TRV (P = .05). We conclude that hydroxyurea therapy may mitigate TRV elevation in children with SCA, possibly as a result of a reduction in hemolysis and improvement in anemia.