bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding Racial and Ethnic Inequities in Uptake and Outcomes Following Multigene Prognostic Testing in Early Breast Cancer: The Promise of Real-World Data
Authors: Wang Xiaoliang , Cho-Phan Cheryl D. , Hoskins Kent F. , Calip Gregory S. 
Published: April 2022

Abstract
In the past decades, multigene prognostic testing, such as Oncotype DX (ODX), has been increasingly used to inform treatment decisions for patients with early-stage breast cancer. This advance in precision oncology has increased existing concerns about differential access to genomic testing across racial and ethnic groups. The investigation by Moore and colleagues, analyzing real-world data from the National Cancer Database, shows that patients of color with breast cancer were less likely to receive ODX testing and Black patients were more likely to have a high risk Recurrence Score (RS) compared with White patients. This study emphasizes that the appropriate adoption of ODX testing is critical to promote equitable cancer care for patients with breast cancer. The reported associations on overall survival across specific racial and ethnic groups provided here give additional insight to the known associations between the ODX RS and outcomes of distant recurrence and cancer-specific mortality. Analyses of contemporary, real-world data from diverse populations with long-term follow-up should continue to keep pace with the expansion of precision breast cancer care to better understand and mitigate potentially widening inequities in genomic testing.
See related article by Moore et al., p. 821
Colonoscopy Findings in FIT+ and mt-sDNA+ Patients versus in Colonoscopy-only Patients: New Hampshire Colonoscopy Registry Data
Authors: Anderson Joseph C. , Robinson Christina M. , Hisey William , Limburg Paul J. , Butterly Lynn F. 
Published: April 2022

Abstract
Few studies compare fecal immunochemical test (FIT) and multi-target stool DNA (mt-sDNA) outcomes in practice. We compared colonoscopy yield following FIT+ or mt-sDNA+ tests to colonoscopies without preceding stool tests in the comprehensive population-based New Hampshire Colonoscopy Registry (NHCR). Outcomes were any neoplasia and an ordered outcome: adenocarcinoma, advanced neoplasia (adenoma/serrated polyp ≥ 1 cm/villous/high-grade dysplasia), nonadvanced neoplasia, or normal. Our total sample included 306 mt-sDNA+ (average age ± SD 67.0 ± 7.9), 276 FIT+ (66.6 ± 8.7), and 50,990 colonoscopy-only patients (61.8 ± 8.1). Among average-risk patients (N = 240 mt-sDNA+, N = 194 FIT+, N = 26,221 colonoscopy only), mt-sDNA+ patients had a higher risk for any neoplasia (67.1%) compared with FIT+ (54.6%, P = 0.00098) or colonoscopy (40.8%, P &lt; 0.0001). Severity of findings and histology subtypes differed across the three groups (P &lt; 0.0001 for both), with a higher yield of advanced findings in mt-sDNA+ patients. In particular, clinically relevant serrated polyps (hyperplastic polyps ≥10 mm/traditional serrated adenomas/sessile serrated polyps) were detected at a higher frequency in mt-sDNA+ patients as compared with FIT+ or colonoscopy-only patients. Even after adjustment, patients with positive mt-sDNA [OR = 2.82; 95% confidence interval (CI), 2.00–4.02] or FIT+ tests (OR = 1.67; 95% CI, 1.19–2.36) were more likely to have histologically more advanced findings than colonoscopy alone. At follow-up colonoscopy, mt-sDNA+ tests were more likely to predict neoplasia than FIT+, largely due to increased detection of serrated polyps.
Prevention Relevance: Colorectal cancer screening options include colonoscopy and stool-based tests, including the fecal immunochemical test (FIT) and the multi-target stool DNA (mt-sDNA) test which, if positive, must be followed by a colonoscopy. Assessing “real-world” outcomes of colonoscopies following positive stool tests can inform their clinical use.
See related Spotlight, p. 417
Classification ofKRAS-Activating Mutations and the Implications for Therapeutic Intervention
Authors: Johnson Christian , Burkhart Deborah L. , Haigis Kevin M. 
Published: April 2022

AbstractMembers of the family of RAS proto-oncogenes, discovered just over 40 years ago, were among the first cancer-initiating genes to be discovered. Of the three RAS family members, KRAS is the most frequently mutated in human cancers. Despite intensive biological and biochemical study of RAS proteins over the past four decades, we are only now starting to devise therapeutic strategies to target their oncogenic properties. Here, we highlight the distinct biochemical properties of common and rare KRAS alleles, enabling their classification into functional subtypes. We also discuss the implications of this functional classification for potential therapeutic avenues targeting mutant subtypes.Significance:Efforts in the recent past to inhibit KRAS oncogenicity have focused on kinases that function in downstream signal transduction cascades, although preclinical successes have not translated to patients with KRAS-mutant cancer. Recently, clinically effective covalent inhibitors of KRASG12C have been developed, establishing two principles that form a foundation for future efforts. First, KRAS is druggable. Second, each mutant form of KRAS is likely to have properties that make it uniquely druggable.
Vive la Résistance: T-cell Immunity in the Protection against SARS-CoV-2 Infection
Authors: McGary Lisa H.F. , Vardhana Santosha A. 
Published: April 2022

Summary
Fahrner and colleagues investigated the immune response of patients with cancer and cancer-free individuals to SARS-CoV-2 and found that a propensity toward an IL5-predominant Th2/Tc2 response was predictive of susceptibility to infection. The results of this study also suggest that a cellular response against the Spike 1 protein receptor binding domain (S1-RBD) region of the SARS-CoV-2 proteome contributes to protection and that mutations in this region may drive viral evolution and immune escape.
See related article by Fahrner et al., p. 958 (8).
Efficient Algorithms Unlock Understanding of Clonal Evolution in Cancer
Authors: Miller Christopher A. 
Published: April 2022

Summary:
In this issue of Blood Cancer Discovery, Wintersinger and colleagues present a new algorithm for quickly and accurately inferring clonal phylogenies from heterogeneous tumors sampled at many timepoints and/or many sites. When coupled with serial sequencing of tumors, this advance promises to increase our understanding of the clonal dynamics that shape tumor evolution and response to therapy.
See related article by Wintersinger et al., p. 208 (9).
Cardiopulmonary Outcomes After the Nuss Procedure in Pectus Excavatum
Authors: Jaroszewski Dawn E. , Farina Juan M. , Gotway Michael B. , Stearns Joshua D. , Peterson Michelle A. , Pulivarthi Venkata S. K. K. , Bostoros Peter , Abdelrazek Ahmad S. , Gotimukul Ashwini , Majdalany David S. , Wheatley‐Guy Courtney M. , Arsanjani Reza 
Published: April 2022

Background
Pectus excavatum is the most common chest wall deformity. There is still controversy about cardiopulmonary limitations of this disease and benefits of surgical repair. This study evaluates the impact of pectus excavatum on the cardiopulmonary function of adult patients before and after a modified minimally invasive repair.

Methods and Results

In this retrospective cohort study, an electronic database was used to identify consecutive adult (aged ≥18 years) patients who underwent cardiopulmonary exercise testing before and after primary pectus excavatum repair at Mayo Clinic Arizona from 2011 to 2020. In total, 392 patients underwent preoperative cardiopulmonary exercise testing; abnormal oxygen consumption results were present in 68% of patients. Among them, 130 patients (68% men, mean age, 32.4±10.0 years) had post‐repair evaluations. Post‐repair tests were performed immediately before bar removal with a mean time between repair and post‐repair testing of 3.4±0.7 years (range, 2.5–7.0). A significant improvement in cardiopulmonary outcomes (
P
<0.001 for all the comparisons) was seen in the post‐repair evaluations, including an increase in maximum, and predicted rate of oxygen consumption, oxygen pulse, oxygen consumption at anaerobic threshold, and maximal ventilation. In a subanalysis of 39 patients who also underwent intraoperative transesophageal echocardiography at repair and at bar removal, a significant increase in right ventricle stroke volume was found (
P
<0.001).

Conclusions
Consistent improvements in cardiopulmonary function were seen for pectus excavatum adult patients undergoing surgery. These results strongly support the existence of adverse cardiopulmonary consequences from this disease as well as the benefits of surgical repair.
Soluble ST2 Is a Sensitive and Specific Biomarker for Fulminant Myocarditis
Authors: Wang Jin , He Mengying , Li Huihui , Chen Yanghui , Nie Xiang , Cai Yuanyuan , Xie Rong , Li Lijuan , Chen Peng , Sun Yang , Li Chenze , Yu Ting , Zuo Houjuan , Cui Guanglin , Miao Kun , Zhao Chunxia , Jiang Jiangang , Heidecker Bettina , Barnett Olga , Maisel Alan , Chen Chen , Wang Dao Wen 
Published: April 2022

Background
The aim of the study was to identify biomarkers that can facilitate early diagnosis and treatment of fulminant myocarditis (FM) in order to reduce mortality.

Methods and Results
First, the expression profiles of circulating cytokines were determined in the plasma samples from 4 patients with FM and 4 controls using human cytokine arrays. The results showed that 39 cytokines from patients with FM were changed at admission. Among them, 8 cytokines returned to normal levels at discharge, including soluble ST2 (sST2), which showed the most marked dynamic changes from disease onset to resolution. Then, in a cohort of 76 patients with FM, 57 patients with acute hemodynamic dysfunction attributable to other causes, and 56 patients with non‐FM, receiver operating characteristic curve analyses suggested that plasma sST2 level was able to differentiate FM from non‐FM or other FM‐unrelated acute heart failure more robustly N‐terminal pro‐B‐type natriuretic peptide or cardiac troponin I. Moreover, longitudinal analysis of plasma sST2 was performed in 10 patients with FM during hospitalization and 16 patients with FM during follow‐up. Finally, the diagnostic value was validated in an additional 26 patients with acute onset of unstable hemodynamics. The cutoff value of plasma sST2 for optimal diagnosis of FM was established at 58.39 ng/mL, where a sensitivity of 85.7% and specificity of 94.7% were achieved.

Conclusions
Elevated sST2 level was associated with mechanical stress or inflammation. Especially, sST2 might be used as a potential biomarker for the rapid diagnosis of FM, which was characterized by strong mechanical stretch stimulation and severe inflammatory response.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03268642.
Impact of Icosapent Ethyl on Cardiovascular Risk Reduction in Patients With Heart Failure in REDUCE‐IT
Authors: Selvaraj Senthil , Bhatt Deepak L. , Steg Ph. Gabriel , Miller Michael , Brinton Eliot A. , Jacobson Terry A. , Juliano Rebecca A. , Jiao Lixia , Tardif Jean‐Claude , Ballantyne Christie M. ,   the REDUCE‐IT Investigators
Published: April 2022

Background
Patients with heart failure (HF) are at high risk for atherosclerotic cardiovascular disease. Studies of atherothrombotic treatments in this population have been disappointing to date. Icosapent ethyl reduced the risk of atherosclerotic cardiovascular disease among a broad array of statin‐treated patients at elevated risk for atherosclerotic cardiovascular disease. Whether the treatment benefits of icosapent ethyl are consistent among those with HF is unknown.

Methods and Results

REDUCE‐IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) randomized 8179 participants, including 1446 (17.7%) patients with a history of HF (icosapent ethyl, N=703; and placebo, N=743). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. We used Cox regression to estimate the risk of outcomes of participants with and without HF. We estimated the placebo‐controlled change in triglycerides and hs‐CRP (high‐sensitivity C‐reactive protein) from baseline to 2 years. Among 1446 patients with HF, median age was 63.0 years, median body mass index was 31.0 kg/m
2
, and more were men (69.3%). Icosapent ethyl reduced triglycerides (median reduction, 33.5 mg/dL, or 15.4%;
P
<0.0001) and hs‐CRP (35.1%;
P
<0.0001) compared with placebo, similar to patients without HF (
P
‐interaction>0.90). The treatment effect on the primary end point in patients with HF history (hazard ratio [HR], 0.87; 95% CI, 0.70–1.08) was consistent with the effects observed in patients without HF history (HR, 0.73; 95% CI, 0.65–0.81) (
P
‐interaction=0.13).

Conclusions
In REDUCE‐IT, icosapent ethyl provided similar improvements in triglyceride levels and hs‐CRP as well as similar cardiovascular risk reduction in patients with and without HF.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01492361.
See further upon the giants: Quantifying intellectual lineage in science
Authors: Jo Woo Seong , Liu Lu , Wang Dashun 
Published: April 2022

Abstract
Newton’s centuries-old wisdom of standing on the shoulders of giants raises a crucial yet underexplored question: Out of all the prior works cited by a discovery, which one is its giant? Here, we develop a discipline-independent method to identify the giant for any individual paper, allowing us to better understand the role and characteristics of giants in science. We find that across disciplines, about 95% of papers appear to stand on the shoulders of giants, yet the weight of scientific progress rests on relatively few shoulders. Defining a new measure of giant index, we find that, while papers with high citations are more likely to be giants, for papers with the same citations, their giant index sharply predicts a paper’s future impact and prize-winning probabilities. Giants tend to originate from both small and large teams, being either highly disruptive or highly developmental. Papers that did not have a giant tend to do poorly on average, yet interestingly, if such papers later became a giant for other papers, they tend to be home-run papers that are highly disruptive to science. Given the crucial importance of citation-based measures in science, the developed concept of giants may offer a useful dimension in assessing scientific impact that goes beyond sheer citation counts.
Violations of the Right to Property in Libya and the Promise of Transitional Justice
Authors: Fowler Alexandra , Radan Mohamed 
Published: April 2022

Abstract
Libya’s Law No. 4 of 1978, which authorised the confiscation of real estate from private owners and its redistribution to other needy citizens, reflected elements of a long debate at the international level about the human right to property. This article examines Law No. 4 against Libya’s obligations under international law and finds that it led to violations of the right to property for which redress still remains outstanding today. Noting also the extensive violations of property rights and displacement in Libya due to civil conflict since 2011, as well as previous ineffective efforts at transitional justice, the article argues for a new concerted attempt at a comprehensive property claims mechanism applying the Pinheiro Principles and complementary international instruments within a broad-ranging transitional justice process. More broadly, Libya’s experience lends weight to calls for encapsulating the right to real property in multilateral treaty form.
On the Bimodality of the Wind-Wave Spectrum: Mean Square Slopes and Azimuthal Overlap Integral
Authors: Romero Leonel , Lubana Kabir 
Published: April 2022

Abstract
We present an investigation of the azimuthal bimodality of the wind-wave spectrum for waves shorter than the dominant scale comparing numerical model solutions of developing waves from idealized experiments using WAVEWATCH III (WW3). The wave solutions were forced with the “exact” Webb–Resio–Tracy (WRT) nonlinear energy fluxes and the direct interaction approximation (DIA) with three different combinations of wind input and breaking dissipation parameterizations. The WRT gives larger azimuthal bimodal amplitudes compared to the DIA regardless of wind input/dissipation. The widely used wind input/dissipation parameterizations (i.e., ST4 and ST6) generally give narrow directional distributions with relatively small bimodal amplitudes and lobe separations compared to field measurements. These biases are significantly improved by the breaking dissipation of Romero (R2019). Moreover, the ratio of the resolved cross- to downwind mean square slope is significantly lower for ST4 and ST6 compared to R2019. The overlap integral relevant for the prediction of microseisms is several orders of magnitude smaller for ST4 and ST6 compared to R2019, which nearly agrees with a semiempirical model.

Significance Statement
Spectral gravity wave models generally cannot accurately predict the directional distribution which impacts their ability to predict the resolved down- and crosswind mean square slopes and the generation of microseisms. Our analysis shows that a directionally narrow spectral energy dissipation, accounting for long-wave–short-wave modulation, can significantly improve the directional distribution of the wind-wave spectrum by coupling to the nonlinear energy fluxes due to wave–wave interactions, which has important implications for improved predictions of the mean square slopes and the generation of microseisms.
Examining Terrain Effects on the Evolution of Precipitation and Vorticity of Typhoon Fanapi (2010) after Departing the Central Mountain Range on Taiwan
Authors: Wu Yao-Chu , Yang Ming-Jen , Rogers Robert F. 
Published: April 2022

Abstract
Typhoon Fanapi (2010) made landfall in Hualien in Taiwan on 0100 UTC 19 September 2010 and left Taiwan on 1200 UTC 19 September 2010, producing heavy rainfall and floods. Fanapi’s eyewall was disrupted by the Central Mountain Range (CMR) and reorganized after leaving the CMR. High-resolution simulations (nested down to 1-km horizontal grid size) using the Advanced Research Weather Research and Forecast (WRF) model, one simulation using the full terrain (CTL) and another set of simulations where the terrain on Taiwan was removed, were analyzed. Precipitation areas were classified into different sub-regions by a convective-stratiform separation algorithm to assess the impact of precipitation structure on Fanapi’s eyewall evolution. The percentage of deep convection increased from 9% to 20% when Fanapi underwent an eyewall reorganization process while departing the CMR. In the absence of terrain, moderate convection occupied most of the convective regions during the period when Fanapi moved across Taiwan Island. The low-level total vorticity stretching within the convective, stratiform and weak echo regions in the no-terrain experiment were of similar magnitudes, but the total vorticity stretching within the convective region at low levels was dominant in the CTL experiment. Total vorticity stretching in the region of deep convection increased after eyewall reorganization, and later became stronger than that in the moderate convection region. In the absence of the CMR, total vorticity stretching in moderate convection dominated. The total vorticity stretching within the deep convective region in the CTL experiment played an essential role in the reorganization of Fanapi’s eyewall through a bottom-up process.
Storm-Scale Predictability and Analysis of the 13 April 2020 Central Savannah River Area Tornado Outbreak
Authors: Kerr Christopher A. , Alsheimer Frank 
Published: April 2022

Abstract
An early morning tornado outbreak occurred on 13 April 2020 in the Central Savannah River Area. Multiple significant tornadoes were reported, resulting in fatalities and injuries. While the operational tornado warnings had positive lead times, the convective mode (quasi-linear convective system) increased the warning decision complexity. The timing of the event [0500–0600 local time (LT)] also made NWS-to-public communication difficult. The experimental NSSL Warn-on-Forecast System (WoFS) was run retrospectively for this case. The WoFS consists of 3–6-h ensemble forecasts initialized every 30 min, and the goals of the system are to bridge the gap between severe weather watches and warnings and to increase warning lead times. Multiple WoFS forecasts were initialized leading up to the first tornado report; those initialized prior to tornado warning issuance have high ensemble probabilities of low-level rotation in the appropriate areas based on subsequent tornado reports. This case highlights another example of the usefulness of WoFS before its eventual transition to operations. Using the WoFS forecasts, kinematic and thermodynamic storm–environment relationships are analyzed using ensemble sensitivity analysis (ESA). The analyses suggest variations in the mesoscale environmental vertical wind profile are not as influential on mesovortex intensity as variations in the thermodynamic environment. Surface observations recorded prior to the tornado outbreak reveal subtle temperature and moisture gradients that may be the impetus for mesovortex intensification and tornadogenesis.
Probabilistic modeling methods for cell-free DNA methylation based cancer classification
Authors: Halla-aho Viivi , Lähdesmäki Harri 
Published: April 2022

Abstract
Background
cfMeDIP-seq is a low-cost method for determining the DNA methylation status of cell-free DNA and it has been successfully combined with statistical methods for accurate cancer diagnostics. We investigate the diagnostic classification aspect by applying statistical tests and dimension reduction techniques for feature selection and probabilistic modeling for the cancer type classification, and we also study the effect of sequencing depth.

Methods
We experiment with a variety of statistical methods that use different feature selection and feature extraction methods as well as probabilistic classifiers for diagnostic decision making. We test the (moderated) t-tests and the Fisher’s exact test for feature selection, principal component analysis (PCA) as well as iterative supervised PCA (ISPCA) for feature generation, and GLMnet and logistic regression methods with sparsity promoting priors for classification. Probabilistic programming language Stan is used to implement Bayesian inference for the probabilistic models.

Results and conclusions
We compare overlaps of differentially methylated genomic regions as chosen by different feature selection methods, and evaluate probabilistic classifiers by evaluating the area under the receiver operating characteristic scores on discovery and validation cohorts. While we observe that many methods perform equally well as, and occasionally considerably better than, GLMnet that was originally proposed for cfMeDIP-seq based cancer classification, we also observed that performance of different methods vary across sequencing depths, cancer types and study cohorts. Overall, methods that seem robust and promising include Fisher’s exact test and ISPCA for feature selection as well as a simple logistic regression model with the number of hyper and hypo-methylated regions as features.