bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Intensive Versus Standard Ambulatory Blood Pressure Control on Cerebrovascular Outcomes in Older People (INFINITY)
Authors: White William B. , Wakefield Dorothy B. , Moscufo Nicola , Guttmann Charles R.G. , Kaplan Richard F. , Bohannon Richard W. , Fellows Douglas , Hall Charles B. , Wolfson Leslie 
Published: October 2019

Background:
Subcortical microvascular disease represented by brain white matter hyperintensity on magnetic resonance imaging is associated with functional decline in older people with hypertension. The effects of 2 levels of 24-hour average systolic blood pressure (BP) on mobility, white matter disease progression, and cognitive function over 3 years were studied.

Methods:
This trial was a prospective, randomized, blinded end-points study in patients ≥75 years of age with systolic hypertension and magnetic resonance imaging evidence of white matter hyperintensity lesions. Patients were randomized to a 24-hour mean systolic BP of ≤130 mm Hg (intensive treatment) versus ≤145 mm Hg (standard treatment) with antihypertensive therapies. Primary study outcomes were changes in mobility (gait speed) and accrual of white matter hyperintensity volume after 3 years. Changes in cognitive function (executive processing) and adverse events were also evaluated.

Results:

In 199 randomized patients, the mean age of the cohort was 80.5 years, and 54% were women; the average 24-hour systolic BP was 149 mm Hg. Goal BPs were achieved after a median treatment period of 3 to 4 months; at that time, the mean 24-hour systolic BP was 127.7 mm Hg in the intensive treatment group and 144.0 mm Hg in the standard treatment group for an average difference of 16.3 mm Hg. Changes in gait speed were not different between treatment groups (0.40±2.0 versus 0.42±2.7 s in the intensive treatment and standard treatment groups, respectively;
P
=0.91), whereas changes from baseline in white matter hyperintensity volumes were smaller (0.29%) in the intensive treatment group compared with the standard treatment group (0.48%;
P
=0.03). Cognitive outcomes also were not different between the treatment groups. Major adverse cardiovascular events were higher in the standard treatment group compared with the intensive treatment group (17 versus 4 patients;
P
=0.01). Falls, with or without injury, and syncope were comparable in the treatment groups.

Conclusions:
Intensive lowering of ambulatory BP reduction in older patients with hypertension did not result in differences in mobility outcomes but was associated with a reduction in accrual of subcortical white matter disease. Over periods >3 years, a reduction in the accumulation of white matter disease may be a factor in conserving function.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01650402.
Comments on “Reconstruction of the Gulf Stream from 1940 to the Present and Correlation with the North Atlantic Oscillation”
Authors: Chi Lequan , Hameed Sultan , Wolfe Christopher L. P. 
Published: October 2019

AbstractThe path of the Gulf Stream as it leaves the continental shelf near Cape Hatteras is marked by a sharp gradient in ocean temperature known as the North Wall. The latitude location of the Gulf Stream North Wall (GSNW) has previously been estimated by subjective analysis of daily maps of sea surface temperatures. Recently, Watelet et al. (2017) presented an objective procedure by fitting an error function to the SST profile across the Gulf Stream at 81 longitude positions. The fit smooths over not only the GSNW but also the much colder waters from the Labrador Sea on the continental shelf. Watelet et al.’s procedure is therefore likely to misidentify the shelf-slope front as the Gulf Stream North Wall, leading to a systematic northward bias the in North Wall position.
Do higher order moments of return distribution provide better decisions in minimum-variance hedging? Evidence from US stock index futures
Authors: Hou Yang (Greg) , Holmes Mark 
Published: October 2019

Using daily S&P 500 spot index and index futures data, this article examines the effects of conditional skewness and kurtosis parameters of a skew-Student density function on dynamic minimum-variance hedging strategies. We find an important role for autoregressive marginal skewness and joint kurtosis in risk management. While static higher order moments improve reductions in variance of hedged portfolios over the case of normality, the inclusion of an autoregressive component significantly extends these improvements. This occurs in both tranquil and tumultuous periods. Furthermore, when transaction costs are considered, taking into account variations of higher order moments retains the best performance. JEL Classification: G11, G13
Wellbeing economics in public policy: A distinctive Australasian contribution?
Authors: Dalziel Paul 
Published: October 2019

AbstractThe ‘Wellbeing Budget’ presented to the New Zealand Parliament in 2019 was widely described as a world-first. This article explores the possibility of a distinctive Australasian contribution to our understanding of wellbeing economics in public policy. The introduction section presents an analytical wellbeing framework showing how human actions draw on services provided by the country’s capital stocks to create and sustain personal and communal wellbeing. The second section chronicles some landmark policy initiatives in Australia and New Zealand for understanding and monitoring wellbeing, culminating in the Wellbeing Budget. The third section highlights four areas for further development: (1) the role of family wellbeing in intergenerational wellbeing, (2) the role of cultural capital in providing foundations for future wellbeing, (3) the role of Indigenous worldviews in enriching understandings of wellbeing and (4) the role of market enterprise in expanding capabilities for wellbeing. These are all areas where Australasian researchers have demonstrated expertise.
Brexit: ‘Revolt’ against the ‘elites’ or Trojan horse for more deregulation?
Authors: Gomez Arana Arantza , Rowe Jay , de Ruyter Alex , Semmens-Wheeler Rebecca , Hill Kimberley 
Published: October 2019

AbstractThis article explores the UK vote in 2016 to exit the European Union, colloquially known as ‘Brexit’. Brexit has been portrayed as a British backlash against globalisation and a desire for a reassertion of sovereignty by the UK as a nation-state. In this context, a vote to leave the European Union has been regarded by its protagonists as a vote to ‘take back control’ to ‘make our own laws’ and ‘let in [only] who we want’. We take a particular interest in the stance of key ‘Brexiteers’ in the UK towards regulation, with the example of the labour market. The article commences by assessing the notion of Brexit as a means to secure further market liberalisation. This analysis is then followed by an account of migration as a key issue, the withdrawal process and likely future trajectory of Brexit. We argue that in contrast to the expectations of those who voted Leave in 2016, the UK as a mid-sized open economy will be a rule-taker and will either remain in the European regulatory orbit, or otherwise drift into the American one.
The Impact of Immunotherapy on Tumor Evolution
Authors: Thomas-Tikhonenko Andrei 
Published: October 2019

Abstract
We have previously described a mechanism of acquired resistance of B-cell acute lymphoblastic leukemia to CD19-directed chimeric antigen receptor T-cell (CART) immunotherapy. It was based on in-frame insertions in or skipping of CD19 exon 2. To distinguish between epitope loss and defects in surface localization, we used retroviral transduction and genome editing to generate cell lines expressing CD19 exon 2 variants (CD19ex2vs) bearing VSV-G tags. These lines were negative by live-cell flow cytometry with an anti-VSV-G antibody and resistant to killing by VSV-G directed antibody-drug conjugates (ADC), suggestive of a defect in surface localization. Indeed, pulse-chase and α-mannosidase inhibitor assays showed that all CD19ex2vs acquired ER-specific high mannose-type sugars, but not complex-type glycans synthesized in Golgi. When fused with GFP, CD19ex2vs (including a mutant lacking the relevant disulfide bond) showed colocalization with ER markers, implicating protein misfolding. Mass spectrometric profiling of CD19-interacting proteins demonstrated that CD19ex2vs fail to bind to the key tetraspanin CD81 and instead interact with ER-resident chaperones such as calnexin and ER transporters involved in antigen presentation. Thus, even the intact domains of CD19ex2vs cannot be easily targeted with ADCs or current CD19 CARTs but could serve as sources of peptides for MHC-restricted presentation and TCR-mediated killing.

Disclosures
Thomas-Tikhonenko: Children's Hospital of Philadelphia: Patents & Royalties.
Clinical Implications and Biomarkers of Clonal Evolution
Authors: Dawson Sarah-Jane 
Published: October 2019

Abstract
Recent technological advances in the detection and characterization of cell free circulating tumor DNA (ctDNA) are providing new opportunities for treatment tailoring based on real-time monitoring of clonal evolution. Circulating biomarkers can provide a "liquid biopsy" alternative to tissue biopsies allowing noninvasive tumor genotyping and the serial analysis of genomic changes from a simple blood test. The emerging clinical benefits of ctDNA analysis in the management of solid tumours has led to an expansion of opportunities in the use of ctDNA for disease monitoring in haematological malignancies. Research in this area has rapidly expanded exploring the role of ctDNA for risk stratification, monitoring tumour burden and identifying the early emergence of treatment resistance. In the management of lymphoma, comprehensive analysis of somatic genomic alterations in plasma DNA has emerged as an important clinical tool. The use of ctDNA analysis to follow tumour specific genomic alterations identified on an individual basis can be used to help identify minimal residual disease post treatment and guide therapeutic decisions. Moreover, ctDNA analysis can been utilized to identify distinct biological subtypes of lymphoma and provide insights into patterns of genomic evolution following treatment. The role of ctDNA as a minimally invasive strategy for disease monitoring has also recently been demonstrated in chronic lymphocytic leukemia (CLL) showing additional potential of this technique in haematological malignancies with a circulating disease component. In CLL, ctDNA analysis can reveal changes in the disease across tissue compartments, including the bone marrow and lymph nodes, providing additional information to that which can be assessed by monitoring the circulating disease alone. Serial ctDNA analysis in CLL can allow clonal dynamics to be monitored over time and can identify the emergence of genomic changes associated with Richter's syndrome. Here, I will focus on the use of ctDNA technology to follow disease burden and track genomic changes in patients receiving novel therapies for lymphoid malignancies, as well as the promises and challenges in developing these tools for clinical application.

Disclosures
No relevant conflicts of interest to declare.
Blood Donation and Iron Deficiency
Authors: Mast Alan E. 
Published: October 2019

Abstract
In the United States about 40,000 people per day donate blood. Donors are from all racial/ethnic backgrounds and range in age from 16 to over 80 years old. They are allowed to repeatedly donate blood every 56 days, as long as they maintain their hemoglobin above 12.5 g/dL for females or 13.0 g/dL for males. Although each donation removes 200-250 mg of iron from the donor, testing for iron deficiency is not performed. Thus, blood donation can be viewed as a large clinical study to examine the physiological effects of repeated phlebotomy of approximately 10% of an individual's blood volume. In addition, blood donors are altruistic by nature and typically are very willing to participate in research studies. We have utilized this rich clinical population to perform studies on iron metabolism and red blood cell biology in an otherwise healthy population. These include a study of over 750,000 donors to define the demographics of anemia. A study detailing the body's response to blood donation, finding that recovery of iron stores takes over 90 days, if the donor takes daily iron pills following donation, and much longer if they do not. Despite this long time for recovery of iron stores, some donors are capable of repeatedly donating blood every 56 days for several years without experiencing a low hemoglobin deferral. Study of these "superdonors" has identified potential associated genetic variants and behaviors that allow frequent donation without development of anemia. Teenagers are allowed to donate blood in the United States at the same 56 day donation frequency and hemoglobin cut-off values as adults even though they have increased iron requirements for continued growth and neurocognitive development. A study detailing the impact of blood donation on teenager hemoglobin and iron stores has found that they are more susceptible to iron deficiency than adults, and, therefore, should have extra protections to prevent donation-induced iron deficiency.

Disclosures
Mast: Novo Nordisk: Research Funding.
New Advances Along the Common Coagulation Pathway
Authors: Camire Rodney M. 
Published: October 2019

Abstract
Hemostasis is achieved through spatially and temporally regulated thrombin generation following vascular injury. Blood coagulation factor V plays an important role in this process as it has a major impact on thrombin production. FV is a large, heavily glycosylated protein sharing homology and domain organization with FVIII (A1-A2-B-A3-C1-C2). It is an inactive procofactor and must be cleaved by thrombin or other proteases to remove the B-domain to yield activated FV (FVa). FVa is a cofactor for FXa in the prothrombinase complex, the enzyme that activates prothrombin. Given the profound effect FVa has on thrombin formation, FV activation represents an important step in hemostasis. Mechanistic studies have revealed that proteolysis within the FV B-domain serves to remove key autoinhibitory sequences that serve to conceal/block FXa binding site(s). These sequences consist of an evolutionary conserved basic region (BR) in the middle of the B-domain and flanking acidic regions (AR1 and AR2) which define the minimal sequences necessary to maintain FV as a procofactor. Removal of either of these regions results in a molecule that can function in prothrombinase. These sequences are intact and present in plasma FV; however, FV released by activated platelets and FV cleaved by FXa represent active forms FV(a) that lack the BR. Recent work indicates these forms of FV(a) may be regulated by TFPIathrough molecular mimicry. TFPIahas a C-terminal basic tail which shares remarkable homology to the FV BR suggesting TFPIamay be an important regulator at the level of prothrombinase. Remarkably, another form of FV missing the BR, resulting from alternative splicing, has been recently described. The FV-East Texas, FV-Amsterdam, and FV-Atlanta alterations all result in the enhanced production of an alternatively spliced form of FV (FV-short) that has most of the B-domain removed including the BR. While these forms of FV should be constitutively active, studies have shown that FV-short circulates in complex with TFPIa. Further, in each of the clinical cases, TFPIalevels are substantially elevated resulting in a bleeding phenotype. While there are several remaining unanswered questions, the FV(a)-TFPIα interaction as well as the identification of FV-short, has the potential to fundamentally alter our understanding of the regulation of the initiation of coagulation.

Disclosures
Camire: Bayer: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees.
A Direct Oral Anticoagulant Edoxaban Enhanced Fibrinolysis Via Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor Activation and Enhancement of Plasmin Generation in Human Plasma
Authors: Morishima Yoshiyuki , Honda Yuko , Furugohri Taketoshi 
Published: October 2019

Abstract
Introduction: Direct oral anticoagulants are as effective as vitamin K antagonists for the treatment of venous thromboembolism and are associated with less bleeding. We have reported that a direct oral factor Xa inhibitor edoxaban exerts a thrombus resolution effect in a rat model of venous thrombosis and enhances tissue plasminogen activator (t-PA)-induced clot lysis in human plasma. However, the mechanism underlying the thrombus resolution effect and fibrinolysis enhancement by edoxaban remains to be determined.
Purposes: To evaluate the effect of edoxaban on plasmin generation during clot lysis in human plasma in vitro. To determine the role of thrombin-activatable fibrinolysis inhibitor (TAFI) in the enhancement of fibrinolysis by edoxaban.
Methods: Pooled human normal plasma or TAFI-deficient plasma (both containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban, an activated TAFI (TAFIa) inhibitor (a fibrinolysis enhancer) potato tuber carboxypeptidase inhibitor (PCI), or vehicle. Clot was induced by adding 2.5 pM tissue factor and 4 µM phospholipids. To monitor the clot formation and lysis, the absorbance of plasma at 405 nm was measured every 30 sec. Clot lysis time was defined as the interval between the time of the midpoint of the clear to maximum turbidity transition and the midpoint of the maximum turbidity to clear transition. Plasmin-α2 antiplasmin complex (PAP) concentration was measured by ELISA as an indicator of plasmin generation.
Results: In normal plasma, PCI accelerated clot lysis and increased plasma PAP concentration. There was a correlation between plasma PAP concentration and percent of clot lysis, indicating that plasma PAP concentration is an appropriate marker of fibrinolysis. Edoxaban at clinically relevant concentrations (75, 150, and 300 ng/mL) significantly shortened clot lysis time and elevated plasma PAP concentration. The additive combined effect of edoxaban and PCI was observed. In TAFI-deficient plasma, clot lysis time was shortened and plasma PAP concentration increased compared with normal plasma. In these samples, the effects of edoxaban and PCI on clot lysis and plasma PAP concentration were markedly diminished as compared with normal plasma.
Conclusions: Edoxaban at clinically relevant concentrations enhanced t-PA-induced clot lysis with increasing plasma PAP concentration in human plasma. The effects of edoxaban on clot lysis and plasmin generation were diminished in TAFI-deficient plasma. A TAFIa inhibitor PCI exerted similar effects. These data suggest that edoxaban enhanced fibrinolysis via inhibition of TAFI activation and enhancement of plasmin generation.

Disclosures
Morishima: Daiichi Sankyo Co., Ltd.: Employment. Honda:Daiichi Sankyo Co., Ltd.: Employment. Furugohri:Daiichi Sankyo Co., Ltd.: Employment.
Recent Survival Trends in Diffuse Large B-Cell Lymphoma (DLBCL)-Did We Make Any Progress Beyond Rituximab?
Authors: Epperla Narendranath , Hallack Neto Abrahão Elias , Costa Luciano J 
Published: October 2019

Abstract
Background
While rituximab revolutionized outcomes in DLBCL, little is known regarding survival improvements at population level beyond the introduction of rituximab. The advent of novel agents, improvements in supportive care and expansion of autologous hematopoietic cell transplantation (auto-HCT) to older individuals may have improved survival of DLBCL patients. We hypothesized that outcomes for patients diagnosed with DLBCL in the U.S. has continued to improve in recent years and intended to measure improvements and identify possible disparities by comparing survival of DLBCL between two consecutive post-rituximab eras.
Methods
We used the population-based SEER-18 registry to calculate the incidence and relative survival rates (RSR) of DLBCL in the U.S. for two consecutive eras since broad availability of rituximab in upfront DLBCL treatment, 2002-2007 (era-1, early years after adoption of rituximab) and 2008-2013 (era-2, availability of novel agents, broader use of auto-HCT and improvement in supportive care). We included adult patients with microscopically confirmed DLBCL as first malignant neoplasm regardless of histologic subtype and survival follow up to the end of 2015.
Results
There were a total of 56,625 DLBCL patients diagnosed between 2002 and 2013, of which 27,306 patients were diagnosed during era-1 and 29,319 during era-2. Median follow up of survivors was 125 months in era-1 and 53 months in era-2. The median age at diagnosis was 66 years with slight male predominance in both the eras. There were no differences in age, gender, race/ethnicity and stage characteristics. There was a slight decline in incidence of DLBCL (era-1 vs. era-2), 8.11 (95% CI=8.01-8.2) vs. 7.82 (95% CI=7.73-7.91) cases per 100,000 persons (P<0.0001). Overall there was a modest improvement in DLBCL RSR, with 5-year RSR improving from 59.5% to 62.5%. Improvement was mostly evident on first year after diagnosis and affected all subsets of patients (Table), but was more pronounced in patients with advanced stage (Figure).
Conclusions
There has been limited improvement in the survival of adult patients with DLBCL beyond the introduction of rituximab, highlighting the need for experimental therapies and calling for the incorporation of novel therapies earlier in treatment, especially for high-risk cases.

Disclosures
Costa: Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Abbvie: Research Funding.