bluuebunny/crossref_metadata_2025_split huggingface dataset:
Childhood Cancer Death When Life Transpires Where High Childhood Poverty Has Persisted for Decades
Authors: Orjuela-Grimm Manuela A. , Beauchemin Melissa P. 
Published: March 2023

AbstractIt is increasingly clear that social determinants of health impact health, well-being, and quality of life. How these factors can impact cancer-related mortality has only recently included the impact on childhood cancer mortality. Hoppman and colleagues examined the impact of historically prevalent poverty on children with cancer in Alabama, a state with elevated pediatric poverty. Their findings provide a revised framework for understanding the contribution of neighborhood-level factors to pediatric cancer outcomes, identifying previously unrecognized gaps and directing us toward new study approaches to better inform interventions at the individual, institutional and policy levels to improve childhood cancer survival. We provide additional commentary on the implications of these findings, unanswered questions, and considerations for the next generation of interventions to improve childhood cancer survival.See related article by Hoppmann et al., p. 380
Detection ofMETPolysomy by Next-generation Sequencing and Its Clinical Relevance forMETInhibitors
Authors: Sun Boyang , Qiu Tian , Zeng Xiaoling , Duan Jianchun , Bai Hua , Xu Jiachen , Li Jin , Li Junling , Hao Xuezhi , Liu Yutao , Lin Lin , Wang Hongyu , Zhang Xin , Zhong Jia , Wang Jie , Ying Jianming , Wang Zhijie 
Published: March 2023

Next-generation sequencing (NGS) has failed to detect mesenchymal epithelial transition factor gene (MET) polysomy in previous studies. We included three non–small cell lung cancer (NSCLC) cohorts in this retrospective study to establish new criteria for detecting MET polysomy and to explore the clinical relevance of MET polysomy. Cohort 1 included 53 patients whose tissues were available for both FISH and NGS assays. Paired plasma and tissue samples were obtained from 261 patients with NSCLC as cohort 2. Cohort 3 included 46 patients with metastatic NSCLC, who presented with MET copy-number gain assessed by NGS. ROC analysis demonstrated that a cut-off point of 2.3 copies achieved the maximum Youden index in discriminating polysomy from normal copy number. Compared with the FISH test for MET polysomy, the sensitivity, specificity, and agreement of NGS were 90%, 90%, and 96.2%, respectively. Following optimization using maximum somatic allele frequency, the sensitivity and specificity of NGS for defining polysomy using plasma samples according to different circulating tumor DNA mutation frequencies were 42% and 63%. The concordance rate between tissue and plasma samples for detecting polysomy was 85%. Regarding the response to MET inhibitor, the median progression-free survival (PFS) of the MET amplification group was significantly higher than that of the polysomy group. The median PFS was similar between the polysomy and normal groups. Our results indicated that NGS may serve as an alternative method for detecting MET polysomy in NSCLC tissues. Moreover, patients with MET polysomy may not benefit from MET inhibitors.Significance:In this study, we established a methodology to differentiate polysomy from normal copy numbers and amplification using NGS. Moreover, this study suggests that it is critical to discriminate MET polysomy from amplification, for the former may dilute the clinical benefit of MET inhibitors.
RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels
Authors: Clifford Bethan L. , Jarrett Kelsey E. , Cheng Joan , Cheng Angela , Seldin Marcus , Morand Pauline , Lee Richard , Chen Mary , Baldan Angel , de Aguiar Vallim Thomas Q. , Tarling Elizabeth J. 
Published: March 2023

Background:
Removal of circulating plasma low-density lipoprotein cholesterol (LDL-C) by the liver relies on efficient endocytosis and intracellular vesicle trafficking. Increasing the availability of hepatic LDL receptors (LDLRs) remains a major clinical target for reducing LDL-C levels. Here, we describe a novel role for RNF130 (ring finger containing protein 130) in regulating plasma membrane availability of LDLR.

Methods:

We performed a combination of gain-of-function and loss-of-function experiments to determine the effect of RNF130 on LDL-C and LDLR recycling. We overexpressed RNF130 and a nonfunctional mutant RNF130 in vivo and measured plasma LDL-C and hepatic LDLR protein levels. We performed in vitro ubiquitination assays and immunohistochemical staining to measure levels and cellular distribution of LDLR. We supplement these experiments with 3 separate in vivo models of RNF130 loss-of-function where we disrupted
Rnf130
using either ASO (antisense oligonucleotides), germline deletion, or AAV CRISPR (adeno-associated virus clustered regularly interspaced short palindromic repeats) and measured hepatic LDLR and plasma LDL-C.

Results:

We demonstrate that RNF130 is an E3 ubiquitin ligase that ubiquitinates LDLR resulting in redistribution of the receptor away from the plasma membrane. Overexpression of RNF130 decreases hepatic LDLR and increases plasma LDL-C levels. Further, in vitro ubiquitination assays demonstrate RNF130–dependent regulation of LDLR abundance at the plasma membrane. Finally, in vivo disruption of
Rnf130
using ASO, germline deletion, or AAV CRISPR results in increased hepatic LDLR abundance and availability and decreased plasma LDL-C levels.

Conclusions:
Our studies identify RNF130 as a novel posttranslational regulator of LDL-C levels via modulation of LDLR availability, thus providing important insight into the complex regulation of hepatic LDLR protein levels.
Circadian Misalignment Impacts the Association of Visceral Adiposity With Elevated Blood Pressure in Adolescents
Authors: Morales-Ghinaglia Natasha , Larsen Michael , He Fan , Calhoun Susan L. , Vgontzas Alexandros N. , Liao Jason , Liao Duanping , Bixler Edward O. , Fernandez-Mendoza Julio 
Published: March 2023

Background:
Although insufficient sleep has been shown to contribute to obesity-related elevated blood pressure, the circadian timing of sleep has emerged as a novel risk factor. We hypothesized that deviations in sleep midpoint, a measure of circadian timing of sleep, modify the association between visceral adiposity and elevated blood pressure in adolescents.

Methods:
We studied 303 subjects from the Penn State Child Cohort (16.2±2.2 years; 47.5% female; 21.5% racial/ethnic minority). Actigraphy-measured sleep duration, midpoint, variability, and regularity were calculated across a 7-night period. Visceral adipose tissue (VAT) was measured with dual-energy X-ray absorptiometry. Systolic blood pressure (SBP) and diastolic blood pressure levels were measured in the seated position. Multivariable linear regression models tested sleep midpoint and its regularity as effect modifiers of VAT on SBP/diastolic blood pressure levels, while adjusting for demographic and sleep covariables. These associations were also examined as a function of being in-school or on-break.

Results:

Significant interactions were found between VAT and sleep irregularity, but not sleep midpoint, on SBP (
P
interaction=0.007) and diastolic blood pressure (
P
interaction=0.022). Additionally, significant interactions were found between VAT and schooldays sleep midpoint on SBP (
P
interaction=0.026) and diastolic blood pressure (
P
interaction=0.043), whereas significant interactions were found between VAT and on-break weekdays sleep irregularity on SBP (
P
interaction=0.034).

Conclusions:
A delayed and an irregular sleep midpoint during school and during free-days, respectively, increase the impact of VAT on elevated blood pressure in adolescents. These data suggest that deviations in the circadian timing of sleep contribute to the increased cardiovascular sequelae associated with obesity and that its distinct metrics require measurement under different entrainment conditions in adolescents.
Specific HIF-2α (Hypoxia-Inducible Factor-2) Inhibitor PT2385 Mitigates Placental Dysfunction In Vitro and in a Rat Model of Preeclampsia (RUPP)
Authors: Colson Arthur , Depoix Christophe Louis , Lambert Isaline , Leducq Camille , Bedin Marie , De Beukelaer Michèle , Gatto Laurent , Loriot Axelle , Peers de Nieuwburgh Maureen , Bouhna Khadija , Baldin Pamela , Hubinont Corinne , Sonveaux Pierre , Debiève Frédéric 
Published: March 2023

Background:
Preeclampsia is one of the leading causes of maternal mortality worldwide and is strongly associated with long-term morbidity in mothers and newborns. Referred to as one of the deep placentation disorders, insufficient remodeling of the spiral arteries during the first trimester remains a major cause of placental dysfunction. Persisting pulsatile uterine blood flow causes abnormal ischemia/reoxygenation phenomenon in the placenta and stabilizes the HIF-2α (hypoxia-inducible factor-2α) in the cytotrophoblasts. HIF-2α signaling impairs trophoblast differentiation and increases sFLT-1 (soluble fms-like tyrosine kinase-1) secretion, which reduces fetal growth and causes maternal symptoms. This study aims to evaluate the benefits of using PT2385—an oral specific HIF-2α inhibitor—to treat severe placental dysfunction.

Methods:

To evaluate its therapeutic potential, PT2385 was first studied in primary human cytotrophoblasts isolated from term placenta and exposed to 2.5% O
2
to stabilize HIF-2α. Viability and luciferase assays, RNA sequencing, and immunostaining were used to analyze differentiation and angiogenic factor balance. The ability of PT2385 to mitigate maternal manifestations of preeclampsia was studied in the selective reduced uterine perfusion pressure model performed in Sprague-Dawley rats.

Results:
In vitro, RNA sequencing analysis and conventional techniques showed that treated cytotrophoblast displayed an enhanced differentiation into syncytiotrophoblasts and normalized angiogenic factor secretion compared with vehicle-treated cells. In the selective reduced uterine perfusion pressure model, PT2385 efficiently decreased sFLT-1 production, thus preventing the onset of hypertension and proteinuria in pregnant dams.

Conclusions:
These results highlight HIF-2α as a new player in our understanding of placental dysfunction and support the use of PT2385 to treat severe preeclampsia in humans.
Change in Smoking Behavior and Outcome After Ischemic Stroke: Post-Hoc Analysis of the SPS3 Trial
Authors: Anadani Mohammad , Turan Tanya N. , Yaghi Shadi , Spiotta Alejandro M. , Gory Benjamin , Sharma Richa , Sheth Kevin N. , de Havenon Adam 
Published: March 2023

Background:
Cigarette smoking is a known risk factor for cardiovascular disease, including ischemic stroke. The literature regarding the rate of persistent smoking after acute ischemic stroke and its effect on subsequent cardiovascular events is scarce. With this study, we aimed to report the rate of persistent smoking after ischemic stroke and the association between smoking status and major cardiovascular outcomes.

Methods:
This is a post-hoc analysis of the SPS3 trial (Secondary Prevention of Small Subcortical Strokes). Patients were divided into 4 groups based on smoking status at trial enrollment: (1) never smokers, (2) former smokers, (3) smokers who quit at 3 months, and (4) persistent smokers. The primary outcome is a major adverse cardiovascular events composite of stroke (ischemic and hemorrhagic), myocardial infarction, and mortality. Outcomes were adjudicated after month 3 of enrollment until an outcome event or the end of study follow-up.

Results:
A total of 2874 patients were included in the study. Of the total cohort, 570 patients (20%) were smokers at enrollment, of whom 408 (71.5%) patients continued to smoke and 162 (28.4%) quit smoking by 3 months. The major adverse cardiovascular events outcome occurred in 18.4%, 12.4%, 16.2%, and 14.4%, respectively, in persistent smokers, smokers who quit, prior smokers, and never smokers. In a model adjusted for age, sex, race, ethnicity, education, employment status, history of hypertension, diabetes, hyperlipidemia, myocardial infarction, and intensive blood pressure randomization arm, the risk of major adverse cardiovascular events, and death were higher in the persistent smokers compared with never smokers (HR for major adverse cardiovascular events: 1.56 [95% CI, 1.16–2.09]; HR for death: 2.0 [95% CI, 2.18–3.12]). The risk of stroke, and MI did not differ according to smoking status

Conclusions:
Compared with never smoking, persistent smoking after acute ischemic stroke was associated with an increased risk of cardiovascular events and death.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00059306.
National Analysis of Health care Related Costs for Health care Workers and Administrators Over the Past Decade: Toward Establishing Sustainable and Cost Effective Health care System
Authors: Abella Maveric , Hayashi Jeffrey , Martinez Brian , Elkbuli Adel 
Published: March 2023

Background We aim to investigate the costs associated with growth in the administrators, health care staff, and physicians to provide direction to establish a sustainable and cost-effective U.S. health care system. Methods Data from the U.S. Bureau of Labor Statistics, particularly the Labor Force Statistics from the Current Population Survey, were utilized from 2009 to 2020. Wages and employment of medical and health service managers (administrators), health care practitioners and technical operations (health care staff), and physicians were used to calculate the total cost. Results Administrator wages have grown similarly to health care staff wages (−4.40 vs −3.01%, P = .454) and physician wages (−4.40 vs −3.29%, P = .672). Additionally, there has been a similar increase in health care staff employment (9.91 vs 14.23%, P = .269) and physician employment (9.91 vs 15.35%, P = .252) compared to administrator employment. Overall, the total growth in administrator cost is similar to the growth in total health care staff cost (6.23 vs 11.80, P = .104) and total physician cost (6.23 vs 13.02%, P = .079). In 2020, physicians had the highest employment growth but the smallest wage increase. Conclusion Although health care staff experienced a greater percent growth in employment and cost per employee than administrators since 2009, the cost per administrator remains greater than that of health care staff. Understanding differences in wages and costs is essential to reduce health care spending without compromising access, delivery, and quality of health care services.
Bidirectional Relationships between Parental Anxiety, Internalizing Symptoms, and Peer Victimization and Aggression among Early Adolescents
Authors: Larrucea-Iruretagoyena Maite , Orue Izaskun 
Published: March 2023

There have been few studies on the bidirectional interaction between the parental and the offspring’s psychological symptoms. It is important to fill in this lacuna to understand the development and vicious cycles of psychological symptoms in the familial context. The objective was to study the bidirectional relationships between parental anxiety, early adolescents’ internalizing symptoms, and peer victimization and aggression. 288 early adolescents (54% girls) between 9 and 15 years ([Formula: see text] = 12.84 and SD = 1.22) and their parents participated in a two-wave bidirectional study. Path analyses showed bidirectional relationships between early adolescents’ internalizing symptoms and peer victimization. Maternal anxiety was preceded by the offspring’s internalizing symptoms. The hypothesized model differed by gender but not age, indicating that the path from peer victimization to peer aggression was stronger in girls. These results contribute to the study of parental and early adolescent symptoms from a multi-informant perspective.
KLRG1 is reduced on NK cells in SLE patients, inversely correlates with disease activity and is modulated by hydroxychloroquine in vitro
Authors: Novelli Lucia , Barbati Cristiana , Capuano Cristina , Recalchi Serena , Ceccarelli Fulvia , Vomero Marta , Alessandri Cristiano , Morrone Stefania , Conti Fabrizio 
Published: March 2023

Objectives Killer cell lectin-like receptor G 1 (KLRG1), a transmembrane receptor with inhibitory capacity expressed in human immune cells, emerged as a novel susceptibility gene for systemic lupus erythematosus (SLE). The aim of this study was to investigate the expression of KLRG1 in SLE patients compared to healthy controls (HC) on both NK and T cells and to evaluate its possible involvement in SLE pathogenesis. Methods Eighteen SLE patients and twelve healthy controls were enrolled. Peripheral blood mononuclear cells (PBMCs) from these patients were phenotypically characterized by immunofluorescence and flow cytometry. The effect of the hydroxychloroquine (HCQ) in vitro on KLRG1 expression and its signaling mediated functions in NK cells were analyzed. Results KLRG1 expression was significantly reduced on the analyzed immune cell populations in SLE patients compared to HC, especially on total NK cells. Moreover, expression of KLRG1 on total NK cells inversely correlated with the SLEDAI-2K. A direct association between KLRG1 expression on NK cells and patients’ treatment with HCQ was observed. In vitro treatment with HCQ increased KLRG1 expression on NK cells. In HC, KLRG1+ NK cells showed reduced degranulation and IFNγ production, while in SLE patient, this inhibition occurred only for the IFNγ production. Conclusion With this study we revealed a reduced expression and an impaired function of KLRG1 on NK cells in SLE patients. These results suggest a possible role of KLRG1 in the pathogenesis of SLE and as a novel biomarker of this disease.
Femtosecond assisted keratopigmentation (FAK) with a 5-millimeter diameter aperture does not affect ocular examination
Authors: Alafaleq Munirah , Garrido Jaime , Ferrari Francis 
Published: March 2023

Aim to assess the feasibility of performing a screening of ocular pathologies after Femtosecond laser Assisted Keratopigmentation (FAK) procedure in normal eyes with the aid of multimodal imaging technologies. Design A Retrospective cohort study. Participants Thirty consecutive international patients (60 eyes) who underwent FAK for purely aesthetic reasons were chosen for this study. Methods Data from medical records of 30 consecutive patients were retrieved after performing tests 6 months after surgery. Clinical examinations were performed by three ophthalmologists. Main outcome measures The main purpose of this study was to see if routine examinations are feasible in patients operated on by the FAK and if the results can be interpreted as easily as in non-operated patients. Results Sixty eyes of thirty consecutive patients that underwent a screening of ocular pathologies at 6 months post FAK were included. 60% were female and 40% were males. Mean age was 36 years +/− 12 years. Screening of ocular pathologies using multimodal imaging tests or clinical examination was performed without any difficulties in acquisition or interpretation in 100% of patients (n = 30) except the endothelial cell count of the corneal periphery which was not possible. The direct examination of the iris periphery was possible at the slit lamp through the translucid pigment. Conclusions The screening of ocular pathologies after purely aesthetic FAK surgery is feasible, except for pathologies of the peripheral posterior cornea.
DALK rejection following vaccination against SARS-CoV-2: 2 case reports
Authors: Swarup Rishi , Mehta Samip 
Published: March 2023

Purpose To report two cases of deep anterior lamellar keratoplasty (DALK) rejection occurring in association with SARS-CoV-2 vaccination. Methods Two patients with prior history of DALK developed immunologic rejection after SARS-CoV-2 vaccination. The first patient, a 15-year-old girl, had a stromal and sub-epithelial rejection nine days after receiving the first dose of the SARS-CoV-2 vaccine BBV152(COVAXINTM, Bharat Biotech, India). The second patient, an 18-year-old male, had a stromal rejection 13 days after receiving the second dose of the ChAdOx1 SARS-CoV-2 vaccine (COVISHIELDTM, Serum Institute of India, India). Results Both patients received frequent topical corticosteroids. The first patient recovered within four weeks and the second patient recovered within two weeks of initiating therapy. Both patients experienced complete resolution of corneal edema and had improvement in their visual acuity. Conclusions DALK rejection is a rare but distinct possibility in patients following SARS-CoV-2 immunization. Further studies are required before establishing clear guidelines regarding risk, follow-up and treatment strategies in such a scenario.
Development of an in-vitro model based on patient vessel geometry for simulated use testing in neurointerventional surgery
Authors: Epshtein Mark , Shazeeb Mohammed Salman , Kühn Anna Luisa , Anagnostakou Vania , Raskett Christopher M. , King Robert M. , Goyal Mayank , Mendes Pereira Vitor , Arthur Adam S. , Puri Ajit S. , Fiorella David , Gounis Matthew J 
Published: March 2023

Background Neurointerventionalists use in-vitro vascular models to train for worst-case scenarios and test new devices in a simulated use environment to predict clinical performance. According to the Food and Drug Administration (FDA), any neurovascular navigation device should be able to successfully navigate two 360-degree turns and two 180-degree turns at the distal portion of the anatomical model. Here, we present a device benchmarking vascular model that complies with FDA recommendations. Methods Our vascular model was assembled from quantitative characterization of 49 patients who underwent CT angiography either for acute ischemic stroke caused by large vessel occlusion or for aneurysm treatment. Following complete characterization of these data, the vascular segments were 3D reconstructed from CT angiograms of 6 selected patients that presented with challenging anatomy. The curvature and total rotational angle were calculated for each segment and the anatomical parts that complied with FDA recommendations were fused together into a single in-vitro model. Results The model was constructed containing two common carotid branches arising from a type two aortic arch and the dimensions of the overall model exceeded the recommendations of the FDA. Two experienced neurointerventionalists tested the model for navigation difficulty using several devices on an in-vitro perfusion system and concluded that the model provided a realistic, challenging scenario. Conclusions This model provides a first prototype designed according to FDA recommendations of cumulative angle while also integrating an aggregation of actual patient-specific anatomy. The availability of this clinically relevant benchmark model presents a potential standardized approach for neurovascular device testing.