bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition
Authors: Schatoff Emma M. , Goswami Sukanya , Zafra Maria Paz , Foronda Miguel , Shusterman Michael , Leach Benjamin I. , Katti Alyna , Diaz Bianca J. , Dow Lukas E. 
Published: July 2019

Abstract

The majority of colorectal cancers show hyperactivated WNT signaling due to inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor. Genetically restoring APC suppresses WNT and induces rapid and sustained tumor regression, implying that reengaging this endogenous tumor-suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and ex vivo organoid cultures, we show that tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control in vivo, but that effective responses are critically dependent on how APC is disrupted. Mutant APC proteins truncated within the mutation cluster region physically engage the destruction complex and suppress the WNT transcriptional program, while APC variants with early truncations (e.g., ApcMin) show limited interaction with AXIN1 and β-catenin, and do not respond to TNKS blockade. Together, this work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/β-catenin signaling, but that APC genotype is a crucial determinant of this response.

Significance:
This study reveals how subtle changes to the mutations in a critical colorectal tumor suppressor, APC, influence the cellular response to a targeted therapy. It underscores how investigating the specific genetic alterations that occur in human cancer can identify important biological mechanisms of drug response and resistance.
This article is highlighted in the In This Issue feature, p. 1325
Effect of Access to Prescribed PCSK9 Inhibitors on Cardiovascular Outcomes
Authors: Myers Kelly D. , Farboodi Niloofar , Mwamburi Mkaya , Howard William , Staszak David , Gidding Samuel , Baum Seth J. , Wilemon Katherine , Rader Daniel J. 
Published: July 2019

Background:
Atherosclerotic cardiovascular disease remains a major cause of death and disability, especially for high-risk familial hypercholesterolemia individuals. PCSK9i (proprotein convertase subtilisin kexin type 9 inhibitors) reduce low-density lipoprotein cholesterol levels and cardiovascular event rates. However, PCSK9i prescriptions are rejected at high rates by payers, and use is often delayed or eventually abandoned as a treatment option. We tested the hypothesis that acute coronary syndromes, coronary interventions, stroke, and cardiac arrest are more prevalent in patients with rejected or abandoned PCSK9i prescriptions than for those with paid PCSK9i prescriptions.

Methods and Results:

We identified 139 036 individuals aged ≥18 years who met the following 3 criteria: prescribed PCSK9i between August 2015 and December 2017, had claims history, and had an established date of exposure for paid, rejected, or abandoned status. To compare the effects of rejected versus paid and abandoned versus paid status, propensity score matching was performed to minimize confounding because of baseline differences in patient groups. Cox regression analyses and incidence density rates for cardiovascular events were estimated on the propensity score-matched cohorts. Patients who received 168 or more days of paid PCSK9i medication within a 12-month period were defined as paid. The hazard ratios for composite cardiovascular events outcome in propensity score-matched analyses were 1.10 (95% CI, 1.01–1.19;
P
=0.02) for rejected versus paid and 1.12 (95% CI, 1.01–1.24;
P
=0.03) for abandoned versus paid. In a stricter analysis where paid patients were defined by receiving 338 or more days of therapy within 12-months, hazard ratio was 1.16 (95% CI, 1.02–1.30;
P
=0.04) for rejected versus paid and 1.21 (95% CI, 1.04–1.38;
P
=0.03) for the abandoned versus paid status. Higher PCSK9i rejection rates were observed with women, racial minorities, and lower-income groups.

Conclusions:
Individuals in the rejected and abandoned cohorts had significantly increased risk of cardiovascular events compared with those in the paid cohort. Rejection, abandonment, and disparities related to PCSK9i prescriptions are related to higher cardiovascular outcome rates.
Use of Percutaneous Coronary Intervention Among Black and White Patients With End‐Stage Renal Disease in the United States
Authors: Nee Robert , Yan Guofen , Yuan Christina M. , Agodoa Lawrence Y. , Norris Keith C. 
Published: July 2019

Background

Racial disparities in invasive cardiac procedures such as percutaneous coronary intervention (
PCI
) in the general population are well documented; however, national‐level data on such disparities in the end‐stage renal disease (
ESRD
) population are lacking. We assessed racial differences in
PCI
between black and white patients with
ESRD
on maintenance dialysis.

Methods and Results

Using the US Renal Data System database, we abstracted Medicare inpatient procedure claims for
PCI
in a cohort of 268 575 Medicare‐primary patients who initiated treatment on maintenance dialysis from January 1, 2009, through June 1, 2013. We conducted Cox regression analyses with
PCI
being the event, adjusted for demographic characteristics, Hispanic ethnicity, cause of
ESRD
, comorbidities, and socioeconomic factors. We also assessed the probability of
PCI
, accounting for death or transplant in competing risk regression models. The crude incidence rate of
PCI
among white patients was 25.8 per 1000 patient‐years versus 15.5 per 1000 patient‐years among black patients. Cox regression analyses demonstrated that black patients were significantly less likely to undergo
PCI
compared with white patients (adjusted hazard ratio: 0.64; 95%
CI
, 0.62–0.67;
P
<0.001). In the competing risk models, the racial gap for
PCI
among black and white patients remained significant with death (subdistribution hazard ratio: 0.81; 95%
CI
, 0.76–0.85;
P
<0.001) or transplant as a competing event (subdistribution hazard ratio: 0.67; 95%
CI,
0.64–0.70;
P
<0.001).

Conclusions

A racial gap exists in
PCI
use among dialysis patients despite having comprehensive coverage with Medicare. These findings persisted despite accounting for demographic, clinical, socioeconomic factors, and death or transplant as competing events.
Age‐Related Trends in Home Blood Pressure, Home Pulse Rate, and Day‐to‐Day Blood Pressure and Pulse Rate Variability Based on Longitudinal Cohort Data: The Ohasama Study
Authors: Satoh Michihiro , Metoki Hirohito , Asayama Kei , Murakami Takahisa , Inoue Ryusuke , Tsubota‐Utsugi Megumi , Matsuda Ayako , Hirose Takuo , Hara Azusa , Obara Taku , Kikuya Masahiro , Nomura Kyoko , Hozawa Atsushi , Imai Yutaka , Ohkubo Takayoshi 
Published: July 2019

Background
Home blood pressure is a more accurate prognosticator than office blood pressure and allows the observation of day‐to‐day blood pressure variability. Information on blood pressure change during the life course links the prediction of blood pressure elevation with age. We prospectively assessed age‐related trends in home blood pressure, home pulse rate, and their day‐to‐day variability evaluated as a coefficient of variation.

Methods and Results

We examined 1665 participants (men, 36.0%; mean age, 56.2 years) from the general population of Ohasama, Japan. A repeated‐measures mixed linear model was used to estimate the age‐related trends. In a mean of 15.9 years, we observed 5438 points of measurements including those at baseline. The home systolic blood pressure linearly increased with age and was higher in men than in women aged <70 years. There was an inverse‐U‐shaped age‐related trend in home diastolic blood pressure. The day‐to‐day home systolic blood pressure linearly increased with age in individuals aged >40 years. However, an U‐shaped age‐related trend in day‐to‐day diastolic blood pressure variability with the nadir point at 65 to 69 years of age was observed. No significant sex differences in the day‐to‐day blood pressure variability were observed (
P
≥0.22). The average and day‐to‐day variability of home pulse rate decreased with age but were lower and higher, respectively, in men than in women.

Conclusions
The current descriptive data are needed to predict future home blood pressure and pulse rate. The data also provide information on the mechanism of day‐to‐day blood pressure and pulse rate variability.
Enacting the Rubric: Teacher Improvements in Windows of High-Stakes
Observation
Authors: Phipps Aaron R. , Wiseman Emily A. 
Published: July 2019

Abstract
Teacher evaluation systems that use in-class observations, particularly in high-stakes settings, are frequently understood as accountability systems intended as nonintrusive measures of teacher quality. Presumably, the evaluation system motivates teachers to improve their practice—an accountability mechanism—and provides actionable feedback for improvement—an information mechanism. No evidence exists, however, establishing the causal link between an evaluation program and daily teacher practices. Importantly, it is unknown how teachers may modify their practice in the time leading up to an unannounced in-class observation, or how they integrate feedback into their practice post-evaluation, a question that fundamentally changes the design and philosophy of teacher evaluation programs. We disentangle these two effects with a unique empirical strategy that exploits random variation in the timing of in-class observations in the Washington, DC, teacher evaluation program IMPACT. Our key finding is that teachers work to improve during periods in which they are more likely to be observed, and they improve with subsequent evaluations. We interpret this as evidence that both mechanisms are at work, and as a result, policy makers should seriously consider both when designing teacher evaluation systems.
The Turn Toward Extraversion: The Changing Psychological Profile of Anglican Clergy
Authors: Francis Leslie J. , Village Andrew , Voas David 
Published: July 2019

Abstract
Recent research has drawn attention to two features associated with extraversion in Anglican ministry. Extraverts are under-represented among Anglican clergy. Extravert leaders are associated with church growth. The present reanalysis of data collected within the Church Growth Research Programme from 1,372 stipendiary clergy serving in the Church of England who were aged 70 or under demonstrated that in recent decades there has been a slight tendency for the Church of England to ordain more extraverts, a feature that cannot simply be explained by the reduced numbers of Anglo-Catholics (who are more likely to be introverts) or growth in charismatic influence. This slight growth, however, has been insufficient to address what may be interpreted as covert discrimination against extraverts in selection for ordination. It is argued that a commitment to inclusivity in recruiting clergy might need to take account of psychological type characteristics of those presenting for selection as much as monitoring their ethnic background.
The Four Lives of Customary International Law
Authors: d’Aspremont Jean 
Published: July 2019

Abstract
This article tells the story of customary international law in the 98 years between the introduction of the draft rules to the new Permanent Court of International Justice and the adoption of the Conclusions on the identification of customary international law by the International Law Commission in 2018. This story is articulated around four moments of rupture and metamorphoses: 1920, 1927, 1986, and 2018. Each of these four metamorphoses originates in powerful interventions by actors resulting in a redefinition of how arguments about the customary status of a rule ought to be made. It is argued that the doctrine of customary international law, by undergoing these four metamorphoses, has gone through 4 different stages: the age of innocence (1920–1927), the age of dualism (1927–1986), the age of turmoil (1986–2018), and the return to innocence (2018-present). The story offered in this article is a story about the four lives of customary international law.
Reflections on Custom Critique and on Functional Equivalents in the Work of Jean d’Aspremont
Authors: Lippold Matthias 
Published: July 2019

Abstract
The present article engages with the custom critique and functional equivalents in the work of Jean d’Aspremont. It reflects on the emphasis given to the distinction between ascertainment and content-determination. If one engages in the politics of law-ascertainment, or the politics of sources and their evaluation, it is submitted here to adopt a contextualized perspective that includes content-determination as well. The article will conclude by pointing out three examples that merit ongoing attention in order to evaluate the distribution of normativity within a system of multiple sources.
Treaty Bodies
Authors: McCall-Smith Kasey 
Published: July 2019

Abstract
This article contributes to existing understandings about the influence of human rights treaty bodies on the development of customary international law. It offers a method of assessing State responses to treaty body jurisprudence for the purposes of determining to what extent the responses push toward the reaffirmation or crystallisation of a customary rule of international law, namely the prohibition against torture. It speaks to the way in which, despite its status as a peremptory norm, the content of the norm is often challenged, but also incrementally expanding due in large part to the way in which treaty bodies engage and guide States both inside and outside of the primary reporting procedures. Ultimately, this article demonstrates that State practice and opinio juris are increasingly influenced by treaty bodies.
Changing Customary Law
Authors: Kleczkowska Agata 
Published: July 2019

Abstract
The unwritten nature of customary international law (CIL) enables it to remain flexible and easily adaptable to changes in States practice and opinio juris, but at the same time may be the source of substantial uncertainties when it comes to the formation, identification and development of customary norms. To investigate this issue, this paper examines the attitudes adopted by States in the aftermath of the airstrikes conducted in Syria by the USA, the UK and France in 2017 and 2018, respectively. The paper is divided into two parts: the first part includes a brief summary of the statements made by States, including the intervening States, after the 2017 and 2018 airstrikes, while the second part is devoted to the analysis of how CIL may have been influenced by the reaction of States to the airstrikes.
Influence of a River Plume on Coastal Upwelling Dynamics: Importance of Stratification
Authors: Chen Zhaoyun , Jiang Yuwu , Wang Jia , Gong Wenping 
Published: July 2019

AbstractSatellite images show that the Pearl River plume is entrained into the upwelling front in the northeastern South China Sea. To understand the processes and extend to other coastal zones, an idealized numerical model is used to investigate the upwelling dynamics in response to the arrival of the river plume. Upon forcing by an upwelling-favorable wind, the model reproduces the upwelling frontal jet with a stratified water column, which takes the river plume far away from the mouth of the estuary. The river plume introduces additional upwelling and downwelling at its inshore and offshore sides (defined as plume-related secondary upwelling circulation), respectively. For the initially unstratified water column, the plume-related secondary upwelling circulation is stronger and extends to deeper water than for the stratified condition. The surface boundary layer thins and the offshore current intensifies in the river plume. The variations in wind-driven current over the deep-water shelf in different stratified conditions are modulated by the vertical profiles of the eddy viscosity, which are shown by a one-dimensional numerical model. Offshore transport is reinforced when the head of the river plume arrives. Thereafter, it is changed by the cross-shore baroclinic geostrophic component of velocity, due to alongshore density variation by the river plume. The horizontal gradient of stress on the two sides of the river plume is responsible for the plume-related secondary upwelling circulation owing to different stress decay scales inside and outside the river plume.
Experiential Learning Processes Informing Climate Change Decision Support
Authors: Kalafatis Scott E. , Neosh Jasmine , Libarkin Julie C. , Whyte Kyle Powys , Caldwell Chris 
Published: July 2019

Abstract
Climate scientists are increasingly called upon to collaborate with policy makers to develop climate science–informed policy decisions. However, there are concerns that existing professional and cultural boundaries will remain persistent barriers to fulfilling the potential promise of these collaborations. The perception that scientists will be learning by doing while pursuing these efforts does little to assuage these concerns because more research is needed into how scientists actually learn to collaborate more effectively. Using interviews with 18 individuals identified by their peers as particularly successful participants in collaborations between Native American Tribes and climate science organizations, this paper offers suggested practices and examines learning processes underlying the development of these suggestions. The development of the list of suggested practices highlights the extent to which having the right attitude, taking the right actions, and cultivating the right processes are intertwined factors associated with success in these collaborations. Analysis of the learning processes underlying interviewees’ suggestions for suggested practices offered five sources of information that frequently led interviewees to reflect on their experiences and gain new knowledge from them. Despite these common trends, each interviewee described a reflection system that they had cultivated to continually monitor and enhance their work in collaborations that was personalized and distinctive from those the other interviewees used. Increased attention to these tailored reflection systems offers a path forward for understanding how experiential learning can most effectively enhance climate change decision support.
Quality control failures exceeding the weekly limit (QC FEWL): a simple tool to improve assay error detection
Authors: Kilpatrick Eric S 
Published: July 2019

Background Even when a laboratory analyte testing process is in control, routine quality control testing will fail with a frequency that can be predicted by the number of quality control levels used, the run frequency and the control rule employed. We explored whether simply counting the number of assay quality control run failures during a running week, and then objectively determining if there was an excess, could complement daily quality control processes in identifying an out-of-control assay. Methods Binomial statistics were used to determine the threshold number of quality control run failures in any rolling week which would statistically exceed that expected for a particular test. Power function graphs were used to establish error detection (Ped) and false rejection rates compared with popular control rules. Results Identifying quality control failures exceeding the weekly limit (QC FEWL) is a more powerful means of detecting smaller systematic (bias) errors than traditional daily control rules (12s, 13s or 13s/22s/R4s) and markedly superior in detecting smaller random (imprecision) errors while maintaining false identification rates below 2%. Error detection rates also exceeded those using a within- and between-run Westgard multirule (13s/22s/41s/10x). Conclusions Daily review of tests shown to statistically exceed their rolling week limit of expected quality control run failures is more powerful than traditional quality control tools at identifying potential systematic and random test errors and so offers a supplement to daily quality control practices that has no requirement for complex data extraction or manipulation.
Professionals’ Implicit Attitudes about the Competence of People Who are Blind
Authors: McDonnall Michele C. , Cmar Jennifer L. , Antonelli Karla , Markoski Kasey M. 
Published: July 2019

Introduction: The purpose of this study was to measure blindness professionals’ implicit attitudes about the competence of people who are blind, compare implicit attitudes of blindness professionals with those of employers in hiring positions, and examine blindness professionals’ implicit attitudes by type of profession and work tenure. Methods: The study included 322 blindness professionals and 450 employers. Participants completed a brief online survey and the Implicit Association Test–Blind/Visually Impaired, which measures implicit attitudes regarding the competence of blind people. Results: On average, blindness professionals exhibited a slight association, whereas employers exhibited a strong association, for sighted with competence and blind with incompetence. Blindness professionals and employers had large, statistically significant differences in implicit attitudes. Blindness professionals’ implicit attitudes did not differ by type of profession, but they differed slightly by work tenure. Discussion: Employers’ strong implicit bias toward sighted and competence may reflect their limited knowledge about blindness and lack of opportunities to interact with blind people. Compared to employers, blindness professionals exhibited a much smaller implicit bias, which may relate to their knowledge about blindness, exposure to successful blind people, and meaningful interactions with blind people across social contexts. Implications for practitioners: Blindness professionals may benefit from increased exposure to highly successful blind role models throughout their professional preparation programs and their careers. Blindness professionals can promote positive attitudes about blindness to the general public and to consumers and their families. During educational opportunities, they could incorporate information about how blind people perform work tasks, which has the potential to improve attitudes about the competence of blind people.