bluuebunny/crossref_metadata_2025_split huggingface dataset:
‘My Advocacy is Not About Me, My Advocacy is About Canadians’: A Qualitative Study of how Caregivers and Patients Influence Regulation of Medical Assistance in Dying in Canada
Authors: Jeanneret Ruthie , Close Eliana , Downie Jocelyn , Willmott Lindy , White Ben P 
Published: April 2024

Abstract
Medical assistance in dying (MAiD) was legalised federally in Canada after the Supreme Court decision in Carter v Canada (Attorney General) [2015] 1 SCR 331. The federal legislative framework for MAiD was established via Bill C-14 in 2016. Caregivers and patients were central to Carter and subsequent litigation and advocacy, which resulted in amendments to the law via Bill C-7 in 2021. Research has primarily focused on the impacts of regulation on caregivers and patients. This qualitative study investigates how caregivers and patients influence law reform and the operation of MAiD practice in Canada (ie, behave as ‘regulatory actors’), using Black’s definition of regulation. We found that caregivers and patients performed sustained, focused, and intentional actions that influenced law reform and the operation of MAiD in practice. Caregivers and patients are not passive objects of Canadian MAiD regulation, and their role in influencing regulation (eg, law reform and MAiD practice) should be supported where this is desired by the person. However, recognising the burdens of engaging in regulatory action to address barriers to accessing MAiD or to quality care, and MAiD system gaps, other regulatory actors (eg, governments) should minimise this burden, particularly where a person engages in regulatory action reluctantly.
Secular evolution of circumbinary 2-planet systems with isotropically varying masses
Authors: Minglibayev Mukhtar Zh , Prokopenya Alexander N , Kosherbayeva Aiken B 
Published: April 2024

ABSTRACT
We investigate the secular evolution of a four-body planetary system, where two planets move around a binary star configuration on quasi-elliptic orbits. It is assumed that the masses of all bodies can change isotropically at different rates and the bodies attract each other according to Newton’s law of universal gravitation. The purpose of this work is to investigate an influence of variability of the masses of the binary stars and their planets on the dynamical evolution of the planetary system. We consider the case of small eccentricities and inclinations of the bodies orbits and assume that their orbits do not intersect during evolution. Differential equations of the perturbed motion in the osculating analogues of canonical Poincaré elements were obtained in a general case of the many-body problem with variable masses in our previous work. Here we solve these equations numerically and investigate the secular evolution of some fictitious circumbinary 2-planet system under assumption that the two stars of the binary system lose their masses independently at different rates. In order to demonstrate the dynamical features of the equations we use the known parameters of the TOI-1338 system. Comparing the results of calculations in the cases of constant and variable masses, we show that the isotropic variability of the masses of bodies can influence substantially the secular perturbation of the orbital elements.
RNAscape: geometric mapping and customizable visualization of RNA structure
Authors: Mitra Raktim , Cohen Ari S , Rohs Remo 
Published: April 2024

AbstractAnalyzing and visualizing the tertiary structure and complex interactions of RNA is essential for being able to mechanistically decipher their molecular functions in vivo. Secondary structure visualization software can portray many aspects of RNA; however, these layouts are often unable to preserve topological correspondence since they do not consider tertiary interactions between different regions of an RNA molecule. Likewise, quaternary interactions between two or more interacting RNA molecules are not considered in secondary structure visualization tools. The RNAscape webserver produces visualizations that can preserve topological correspondence while remaining both visually intuitive and structurally insightful. RNAscape achieves this by designing a mathematical structural mapping algorithm which prioritizes the helical segments, reflecting their tertiary organization. Non-helical segments are mapped in a way that minimizes structural clutter. RNAscape runs a plotting script that is designed to generate publication-quality images. RNAscape natively supports non-standard nucleotides, multiple base-pairing annotation styles and requires no programming experience. RNAscape can also be used to analyze RNA/DNA hybrid structures and DNA topologies, including G-quadruplexes. Users can upload their own three-dimensional structures or enter a Protein Data Bank (PDB) ID of an existing structure. The RNAscape webserver allows users to customize visualizations through various settings as desired. URL: https://rnascape.usc.edu/.
A method to comprehensively identify germline SNVs, INDELs and CNVs from whole exome sequencing data of BRCA1/2 negative breast cancer patients
Authors: Bianchi Andrea , Zelli Veronica , D’Angelo Andrea , Di Matteo Alessandro , Scoccia Giulia , Cannita Katia , Dimas Antigone S , Glentis Stavros , Zazzeroni Francesca , Alesse Edoardo , Di Marco Antinisca , Tessitore Alessandra 
Published: April 2024

Abstract
In the rapidly evolving field of genomics, understanding the genetic basis of complex diseases like breast cancer, particularly its familial/hereditary forms, is crucial. Current methods often examine genomic variants—such as Single Nucleotide Variants (SNVs), insertions/deletions (Indels), and Copy Number Variations (CNVs)—separately, lacking an integrated approach. Here, we introduced a robust, flexible methodology for a comprehensive variants’ analysis using Whole Exome Sequencing (WES) data. Our approach uniquely combines meticulous validation with an effective variant filtering strategy. By reanalyzing two germline WES datasets from BRCA1/2 negative breast cancer patients, we demonstrated our tool’s efficiency and adaptability, uncovering both known and novel variants. This contributed new insights for potential diagnostic, preventive, and therapeutic strategies. Our method stands out for its comprehensive inclusion of key genomic variants in a unified analysis, and its practical resolution of technical challenges, offering a pioneering solution in genomic research. This tool presents a breakthrough in providing detailed insights into the genetic alterations in genomes, with significant implications for understanding and managing hereditary breast cancer.
Mendelian Randomization Analysis of the Causal Effect of Cigarette Smoking on Hospital Costs
Authors: Dixon Padraig , Sallis Hannah , Munafò Marcus , Davey Smith George , Howe Laura 
Published: April 2024

Abstract

Introduction
Knowledge of the impact of smoking on health care costs is important for establishing the external effects of smoking and for evaluating policies intended to modify this behavior. Conventional analysis of this association is difficult because of omitted variable bias, reverse causality, and measurement error.

Aims and Methods
We approached these challenges using a Mendelian Randomization study design; genetic variants associated with smoking behaviors were used in instrumental variables models with inpatient hospital costs (calculated from electronic health records) as the outcome. We undertook genome-wide association studies to identify genetic variants associated with smoking initiation and a composite smoking index (reflecting cumulative health impacts of smoking) on up to 300 045 individuals (mean age: 57 years at baseline, range 39–72 years) in the UK Biobank. We followed individuals up for a mean of 6 years.

Results
Genetic liability to initiate smoking (ever vs. never smoking) was estimated to increase mean per-patient annual inpatient hospital costs by £477 (95% confidence interval (CI): £187 to £766). A one-unit change in genetic liability to the composite smoking index (range: 0–4.0) increased inpatient hospital costs by £204 (95% CI: £105 to £303) per unit increase in this index. There was some evidence that the composite smoking index causal models violated the instrumental variable assumptions, and all Mendelian Randomization models were estimated with considerable uncertainty. Models conditioning on risk tolerance were not robust to weak instrument bias.

Conclusions
Our findings have implications for the potential cost-effectiveness of smoking interventions.

Implications
We report the first Mendelian Randomization analysis of the causal effect of smoking on health care costs. Using two smoking phenotypes, we identified substantial impacts of smoking on inpatient hospital costs, although the causal models were associated with considerable uncertainty. These results could be used alongside other evidence on the impact of smoking to evaluate the cost-effectiveness of antismoking interventions and to understand the scale of externalities associated with this behavior.
Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens
Authors: Saad Eddy , Gebrael Georges , Semaan Karl , Eid Marc , Saliby Renée Maria , Labaki Chris , Sayegh Nicolas , Wells J Connor , Takemura Kosuke , Ernst Matthew Scott , Lemelin Audreylie , Basappa Naveen S , Wood Lori A , Powles Thomas , Ernst D Scott , Lalani Aly-Khan A , Agarwal Neeraj , Xie Wanling , Heng Daniel Y C , Choueiri Toni K 
Published: April 2024

Abstract

Background
Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens.

Materials and Methods
Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model.

Results
A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (P = .027) but not for TTF (P = .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, P = .02).

Conclusion
Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.
Three-dimensional reconstruction and multiomics analysis reveal a unique pattern of embryogenesis in Ginkgo biloba
Authors: Ma Lingyu , Hu Zijian , Shen Weiwei , Zhang Yingying , Wang Guangchao , Chang Bang , Lu Jinkai , Cui Yaning , Xu Huimin , Feng Yun , Jin Biao , Zhang Xi , Wang Li , Lin Jinxing 
Published: April 2024

Abstract
Ginkgo (Ginkgo biloba L.) is one of the earliest extant species in seed plant phylogeny. Embryo development patterns can provide fundamental evidence for the origin, evolution, and adaptation of seeds. However, the architectural and morphological dynamics during embryogenesis in G. biloba remain elusive. Herein, we obtained over 2,200 visual slices from 3 stages of embryo development using micro-computed tomography imaging with improved staining methods. Based on 3-dimensional (3D) spatiotemporal pattern analysis, we found that a shoot apical meristem with 7 highly differentiated leaf primordia, including apical and axillary leaf buds, is present in mature Ginkgo embryos. 3D rendering from the front, top, and side views showed 2 separate transport systems of tracheids located in the hypocotyl and cotyledon, representing a unique pattern of embryogenesis. Furthermore, the morphological dynamic analysis of secretory cavities indicated their strong association with cotyledons during development. In addition, we identified genes GbLBD25a (lateral organ boundaries domain 25a), GbCESA2a (cellulose synthase 2a), GbMYB74c (myeloblastosis 74c), GbPIN2 (PIN-FORMED 2) associated with vascular development regulation, and GbWRKY1 (WRKYGOK 1), GbbHLH12a (basic helix–loop–helix 12a), and GbJAZ4 (jasmonate zim-domain 4) potentially involved in the formation of secretory cavities. Moreover, we found that flavonoid accumulation in mature embryos could enhance postgerminative growth and seedling establishment in harsh environments. Our 3D spatial reconstruction technique combined with multiomics analysis opens avenues for investigating developmental architecture and molecular mechanisms during embryogenesis and lays the foundation for evolutionary studies of embryo development and maturation.
Inhibition effect of copper-bearing metals on arterial neointimal hyperplasia via the AKT/Nrf2/ARE pathway in vitro and in vivo
Authors: Wang Peng , Xu Xiaohe , Gu Guisong , Guo Qianwen , Rao Yanzhi , Yang Ke , Xi Tong , Yuan Yonghui , Chen Shanshan , Qi Xun 
Published: April 2024

Abstract
In-stent restenosis can be caused by the activation, proliferation and migration of vascular smooth muscle cells (VSMCs), which affects long-term efficacy of interventional therapy. Copper (Cu) has been proved to accelerate the endothelialization and reduce thrombosis formation, but little is known about its inhibition effect on the excessive proliferation of VSMCs. In this study, 316L-Cu stainless steel and L605-Cu cobalt-based alloy with varying Cu content were fabricated and their effects on surface property, blood compatibility and VSMCs were studied in vitro and in vivo. CCK-8 assay and EdU assay indicated that the Cu-bearing metals had obvious inhibitory effect on proliferation of VSMCs. Blood clotting and hemolysis tests showed that the Cu-bearing metals had good blood compatibility. The inhibition effect of the Cu-bearing metals on migration of cells was detected by Transwell assay. Further studies showed that Cu-bearing metals significantly decreased the mRNA expressions of bFGF, PDGF-B, HGF, Nrf2, GCLC, GCLM, NQO1 and HO1. The phosphorylation of AKT and Nrf2 protein expressions in VSMCs were significantly decreased by Cu-bearing metals. Furthermore, it was also found that SC79 and TBHQ treatments could recover the protein expressions of phospho-AKT and Nrf2, and their downstream proteins as well. Moreover, 316L-Cu stent proved its inhibitory action on the proliferation of VSMCs in vivo. In sum, the results demonstrated that the Cu-bearing metals possessed apparent inhibitory effect on proliferation and migration of VSMCs via regulating the AKT/Nrf2/ARE pathway, showing the Cu-bearing metals as promising stent materials for long-term efficacy of implantation.
Risk of Post-Intubation Laryngotracheal Stenosis With Respect to COVID-19 Status in a Large Multicenter Cohort Cross-Sectional Study
Authors: Gray Raluca , Pradhan Prajwal Mani , Hoffmeister Jesse , Misono Stephanie , Cho Roy , Tignanelli Christopher 
Published: April 2024

OBJECTIVES:
Occurrence of post-intubation laryngotracheal stenosis (LTS) with respect to COVID-19 status.

DESIGN:
Retrospective cross-sectional inpatient database.

SETTING:
Eleven Midwest academic and community hospitals, United States.

PATIENTS:
Adults, mechanically ventilated, from January 2020 to August 2022, who were subsequently readmitted within 6 months with a new diagnosis of LTS.

INTERVENTIONS:
None.

MEASUREMENTS AND MAIN RESULTS:
Six thousand eight hundred fifty-one COVID-19 negative and 1316 COVID-19 positive patients were intubated and had similar distribution by age (median 63.77 vs. 63.16 yr old), sex (male, 60.8%; n = 4173 vs. 60%; n = 789), endotracheal tube size (≥ 7.5, 75.8%; n = 5192 vs. 75.5%; n = 994), and comorbidities. The ICU length of stay (median [interquartile range (IQR)], 7.23 d [2.13–16.67 d] vs. 3.95 d [1.91–8.88 d]) and mechanical ventilation days (median [IQR], 5.57 d [1.01–14.18 d] vs. 1.37 d [0.35–4.72 d]) were longer in the COVID-19 positive group. The occurrence of LTS was double in the COVID-19 positive group (12.7%, n = 168 vs. 6.4%, n = 440; p < 0.001) and was most commonly diagnosed within 60 days of intubation. In multivariate analysis, the risk of LTS increased by 2% with each additional ICU day (hazard ratio [HR], 1.02; 95% CI, 1.02–1.03; p < 0.001), by 3% with each additional day of ventilation (HR, 1.03; 95% CI, 1.02–1.04; p < 0.001), and by 52% for each additional reintubation (HR, 1.52; 95% CI, 1.36–1.71; p < 0.001). We observed no significant association COVID-19 status and risk of LTS.

CONCLUSIONS:
The occurrence of post-intubation LTS was double in a COVID-19 positive cohort, with higher risk with increasing number of days intubated, days in the ICU and especially with the number of reintubations. COVID-19 status was not an independent risk factor for LTS.
Pinch Grafting: A Systematic Review of Modern Perspectives and Applications in Dermatologic Surgery and Wound Healing
Authors: Jeha George M. , Hill Emma , Taylor Laura , Davis Michael , Greenway Hubert T. , Kelley Benjamin 
Published: April 2024

BACKGROUND
Pinch grafting has experienced a resurgence in interest in recent years, stemming from its simplicity, safety, and potential in restoring tissue integrity. While historically employed for chronic nonhealing wounds, pinch grafts have shown promise following surgical procedures, particularly those involving the lower extremities.

OBJECTIVE
To systematically review the literature and present an updated overview of the current applications of pinch grafting.

METHODS
A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In collaboration with a medical reference librarian, the PubMed, Embase, Scopus, and Web of Science databases were searched for studies reporting on the use of pinch grafting from 2000 onward. The references of each included article were also screened.

RESULTS
Ten articles met final inclusion criteria. In total, 300 patients underwent pinch grafting for treatment of skin ulceration, while an additional 35 cases were performed as an alternative to primary closure following skin cancer resection. Overall, pinch grafting was safe and well tolerated, with minimal adverse outcomes reported.

CONCLUSION
Pinch grafting is a safe, straightforward, and effective technique to promote the healing of chronic wounds. While the procedure shows early promise in emerging applications within dermatologic surgery, only about 10% of the reported cases involved this indication, reflecting a need for further research in this area.
Comparing PCSK9 Monoclonal Antibody Treatment Strategies Following Myocardial Infarction Using Negative Control Outcomes: A Target Trial Emulation Study
Authors: Sloot Rosa , Breskin Alexander , Colantonio Lisandro D. , Allmon Andrew G. , Yu Ying , Sakhuja Swati , Chen Ligong , Muntner Paul , Brookhart M. Alan , Dhalwani Nafeesa 
Published: April 2024

Background:
Initiation of proprotein convertase subtilisin/kexin type 9 monoclonal antibody (PCSK9 mAb) for lipid-lowering following myocardial infarction (MI) is likely affected by patients’ prognostic factors, potentially leading to bias when comparing real-world treatment effects.

Methods:
Using target-trial emulation, we assessed potential confounding when comparing two treatment strategies post-MI: initiation of PCSK9 mAb within 1 year and no initiation of PCSK9 mAb. We identified MI hospitalizations during July 2015–June 2020 for patients aged ≥18 years in Optum’s de-identified Clinformatics Data Mart (CDM) and MarketScan, and those aged ≥66 in the US Medicare claims database. We estimated a 3-year counterfactual cumulative risk and risk difference (RD) for 10 negative control outcomes using the clone–censor–weight approach to address time-varying confounding and immortal person-time.

Results:
PCSK9 mAb initiation within 1-year post-MI was low (0.7% in MarketScan and 0.4% in both CDM and Medicare databases). In CDM, there was a lower risk for cancer (RD = −3.6% [95% CI: −4.3%, −2.9%]), decubitus ulcer (RD = −7.7% [95% CI: −11.8%, −3.7%]), fracture (RD = −8.1% [95% CI: −9.6%, −6.6%]), influenza vaccine (RD = −9.3% [95% CI: −17.5%, −1.1%]), and visual test (RD = −0.6% [95% CI: −0.7%, −0.6%]) under the PCSK9 mAb initiation versus no initiation strategy. Similar differences persisted in the MarketScan and Medicare databases. In each database, ezetimibe and low-density lipoprotein testing were unbalanced between treatment strategies.

Conclusion:
A comparative effectiveness study of these treatments using the current approach would likely bias results due to the low number of PCSK9 mAb initiators.
Defining the Safe Entry Point in Deep Plane Facelifting with Novel Landmark for the Buccal Branch of the Facial Nerve
Authors: Medhurst Ryan , Tremblay Cory , Marrelli Kristina , Best Corliss , Jadeski Lorraine , Brace Matthew 
Published: April 2024

Background:
In deep facial surgery, accurate preoperative landmarking of branches of the facial nerve is helpful in avoiding inadvertent facial nerve injury. The objective of our study was to determine the accuracy at which the intersection point of two bisecting lines that join facial surface landmarks can be used to accurately locate the buccal branch(es) of the facial nerve, specifically at the deep plane entry point (ie, intercept landmark).

Methods:
Thirty-three cadavers were dissected to determine the position of the buccal rami relative to the intercept.

Results:
Buccal rami crossed the intercept in 12.12% of specimens (0 mm from intercept, n = 4). Buccal rami passed superiorly in 66.67% of specimens (3.71 ± 3.28 mm from intercept, n = 7) and inferiorly in 21.21% of specimens (2.44 ± 0.92 mm from intercept, n = 7). Noteworthy, buccal rami were located within 1 cm of the intercept landmark with 96.97% accuracy (32/33 cadavers).

Conclusions:
These data suggest that this novel intercept (1) reliably locates the buccal branch of the facial nerve as it courses distal to the parotid gland, and (2) helps define a “safe zone” for entry into the deep plane where the likelihood of encountering the facial nerve is extremely low.
Optimizing Aesthetic Outcomes in Autologous Breast Reconstruction: 20 Pearls for Practice
Authors: Sinik Lauren M. , Le Audrey , Ehirim Henrietta , Collins Meredith S. 
Published: April 2024

Summary:
Autologous breast reconstruction with a deep inferior epigastric artery perforator (DIEP) flap is an excellent option for many patients proceeding with mastectomy for surgical management of their breast cancer. As microsurgical techniques and results improve and ensure consistent flap survival, optimizing aesthetic outcomes may become a primary focus. This article outlines 20 tips that can improve aesthetic results in DIEP flap breast reconstruction, based on our senior author’s 8-year career in microsurgical breast reconstruction, with an emphasis on enhanced cosmesis. We highlight tips on preoperative planning, intraoperative, and revision stages of the reconstruction and provide a schematic for integrating the tips into a reader’s microsurgical breast reconstruction practice.