bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma
Authors: Xiao Lin , Somers Klaartje , Murray Jayne , Pandher Ruby , Karsa Mawar , Ronca Emma , Bongers Angelika , Terry Rachael , Ehteda Anahid , Gamble Laura D. , Issaeva Natalia , Leonova Katerina I. , O'Connor Aisling , Mayoh Chelsea , Venkat Pooja , Quek Hazel , Brand Jennifer , Kusuma Frances K. , Pettitt Jessica A. , Mosmann Erin , Kearns Adam , Eden Georgina , Alfred Stephanie , Allan Sophie , Zhai Lei , Kamili Alvin , Gifford Andrew J. , Carter Daniel R. , Henderson Michelle J. , Fletcher Jamie I. , Marshall Glenn , Johnstone Ricky W. , Cesare Anthony J. , Ziegler David S. , Gudkov Andrei V. , Gurova Katerina V. , Norris Murray D. , Haber Michelle 
Published: May 2021

Abstract

Purpose:
We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma.

Experimental Design:
The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction.

Results:
The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination.

Conclusions:
The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.
Effects of Sacubitril/Valsartan on Serum Lipids in Heart Failure With Preserved Ejection Fraction
Authors: Selvaraj Senthil , Claggett Brian L. , Packer Milton , Zannad Faiez , Anand Inder S. , Pieske Burkert , Zhao Ziqiang , Shi Victor C. , Lefkowitz Martin P. , McMurray John J. V. , Solomon Scott D. 
Published: May 2021

Background
Dyslipidemia is common in heart failure with preserved ejection fraction. Sacubitril/valsartan improves glycemic control and augments natriuretic peptide signaling, providing mechanisms by which sacubitril/valsartan may affect serum lipids. However, empiric data on these effects are lacking.

Methods and Results

We analyzed 4774 participants from PARAGON‐HF (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor With Angiotensin‐Receptor Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction) with available screening lipids. During follow‐up visits, we analyzed the treatment effect on lipid levels and assessed for interaction by baseline lipid levels. At the 16‐week visit, we adjusted these treatment effects for the change in several biomarkers (including hemoglobin A
1c
and urinary cyclic guanosine monophosphate/creatinine [a biomarker of natriuretic peptide activation]). The average age was 73±8 years, 52% were women, 43% had diabetes mellitus, and 64% were on statin therapy. Compared with valsartan, sacubitril/valsartan reduced triglycerides −5.0% (95% CI, −6.6% to −3.5%), increased high‐density lipoprotein cholesterol +2.6% (95% CI, +1.7% to +3.4%), and increased low‐density lipoprotein cholesterol +1.7% (95% CI, +0.4% to +3.0%). Sacubitril/valsartan reduced triglycerides most among those with elevated baseline levels (triglycerides≥200 mg/dL) (
P
‐interaction<0.001), and at 16 weeks by −13.0% (95% CI, −18.1% to −7.6%), or −29.9 (95% CI, −44.3 to −15.5) mg/dL, in this group. Adjusting for the change in urinary cyclic guanosine monophosphate/creatinine significantly attenuated treatment effects on triglycerides and high‐density lipoprotein cholesterol, but not low‐density lipoprotein cholesterol, while adjusting for other biomarkers did not significantly alter the treatment effects.

Conclusions
Sacubitril/valsartan significantly reduces triglycerides compared with valsartan, an effect that was nearly threefold stronger in those with elevated baseline triglycerides. Modest increases in high‐density lipoprotein cholesterol and low‐density lipoprotein cholesterol cholesterol were also observed with therapy. The underlying mechanism(s) of changes in high‐density lipoprotein cholesterol and triglycerides are related to sacubitril/valsartan’s effects on natriuretic peptide activity.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01920711.
Out‐of‐Pocket Annual Health Expenditures and Financial Toxicity From Healthcare Costs in Patients With Heart Failure in the United States
Authors: Wang Stephen Y. , Valero‐Elizondo Javier , Ali Hyeon‐Ju , Pandey Ambarish , Cainzos‐Achirica Miguel , Krumholz Harlan M. , Nasir Khurram , Khera Rohan 
Published: May 2021

Background
Heart failure (HF) poses a major public health burden in the United States. We examined the burden of out‐of‐pocket healthcare costs on patients with HF and their families.

Methods and Results
In the Medical Expenditure Panel Survey, we identified all families with ≥1 adult member with HF during 2014 to 2018. Total out‐of‐pocket healthcare expenditures included yearly care‐specific costs and insurance premiums. We evaluated 2 outcomes of financial toxicity: (1) high financial burden—total out‐of‐pocket healthcare expense to postsubsistence income ratio of >20%, and (2) catastrophic financial burden with the ratio of >40%—a bankrupting expense defined by the World Health Organization. There were 788 families in the Medical Expenditure Panel Survey with a member with HF representing 0.54% (95% CI, 0.48%–0.60%) of all families nationally. The overall mean annual out‐of‐pocket healthcare expenses were $4423 (95% CI, $3908–$4939), with medications and health insurance premiums representing the largest categories of cost. Overall, 14% (95% CI, 11%–18%) of families experienced a high burden and 5% (95% CI, 3%–6%) experienced a catastrophic burden. Among the two‐fifths of families considered low income, 24% (95% CI, 18%–30%) experienced a high financial burden, whereas 10% (95% CI, 6%–14%) experienced a catastrophic burden. Low‐income families had 4‐fold greater risk‐adjusted odds of high financial burden (odds ratio [OR] , 3.9; 95% CI, 2.3–6.6), and 14‐fold greater risk‐adjusted odds of catastrophic financial burden (OR, 14.2; 95% CI, 5.1–39.5) compared with middle/high‐income families.

Conclusions
Patients with HF and their families experience large out‐of‐pocket healthcare expenses. A large proportion encounter financial toxicity, with a disproportionate effect on low‐income families.
Phylogenetic history influences convergence for a specialized ecology: comparative skull morphology of African burrowing skinks (Squamata; Scincidae)
Authors: Stepanova Natasha , Bauer Aaron M. 
Published: May 2021

Abstract
Background
Skulls serve many functions and as a result, are subject to many different evolutionary pressures. In squamates, many fossorial species occupy a unique region of skull morphospace, showing convergence across families, due to modifications related to head-first burrowing. As different substrates have variable physical properties, particular skull shapes may offer selective advantages in certain substrates. Despite this, studies of variation within burrowers have been limited and are typically focused on a single origin of fossoriality. We focused on seven skink genera (Acontias, Typhlosaurus, Scelotes, Sepsina, Feylinia, Typhlacontias, and Mochlus; 39 sp.) from southern Africa, encompassing at least three independent evolutions of semi-fossoriality/fossoriality. We used microCT scans and geometric morphometrics to test how cranial and mandibular shape were influenced by phylogenetic history, size, and ecology. We also qualitatively described the skulls of four species to look at variation across phylogenetic and functional levels, and assess the degree of convergence.

Results
We found a strong effect of phylogenetic history on cranial and mandibular shape, with size and substrate playing secondary roles. There was a clear gradient in morphospace from less specialized to more specialized burrowers and burrowers in sand were significantly different from those in other substrates. We also created an anatomical atlas for four species with each element described in isolation. Every bone showed some variation in shape and relative scaling of features, with the skull roofing bones, septomaxilla, vomer, and palatine showing the most variation. We showed how broad-scale convergence in traits related to fossoriality can be the result of different anatomical changes.

Conclusions
Our study used geometric morphometrics and comparative anatomy to examine how skull morphology changes for a highly specialized and demanding lifestyle. Although there was broad convergence in both shape and qualitative traits, phylogenetic history played a large role and much of this convergence was produced by different anatomical changes, implying different developmental pathways or lineage-specific constraints. Even within a single family, adaptation for a specialized ecology does not follow a singular deterministic path.
A population‐based study to develop juvenile arthritis case definitions for administrative health data using model‐based dynamic classification
Authors: Feely Allison , Lim Lily SH , Jiang Depeng , Lix Lisa M. 
Published: May 2021

Abstract
Background
Previous research has shown that chronic disease case definitions constructed using population-based administrative health data may have low accuracy for ascertaining cases of episodic diseases such as rheumatoid arthritis, which are characterized by periods of good health followed by periods of illness. No studies have considered a dynamic approach that uses statistical (i.e., probability) models for repeated measures data to classify individuals into disease, non-disease, and indeterminate categories as an alternative to deterministic (i.e., non-probability) methods that use summary data for case ascertainment. The research objectives were to validate a model-based dynamic classification approach for ascertaining cases of juvenile arthritis (JA) from administrative data, and compare its performance with a deterministic approach for case ascertainment.

Methods
The study cohort was comprised of JA cases and non-JA controls 16 years or younger identified from a pediatric clinical registry in the Canadian province of Manitoba and born between 1980 and 2002. Registry data were linked to hospital records and physician billing claims up to 2018. Longitudinal discriminant analysis (LoDA) models and dynamic classification were applied to annual healthcare utilization measures. The deterministic case definition was based on JA diagnoses in healthcare use data anytime between birth and age 16 years; it required one hospitalization ever or two physician visits. Case definitions based on model-based dynamic classification and deterministic approaches were assessed on sensitivity, specificity, and positive and negative predictive values (PPV, NPV). Mean time to classification was also measured for the former.

Results
The cohort included 797 individuals; 386 (48.4 %) were JA cases. A model-based dynamic classification approach using an annual measure of any JA-related healthcare contact had sensitivity = 0.70 and PPV = 0.82. Mean classification time was 9.21 years. The deterministic case definition had sensitivity = 0.91 and PPV = 0.92.

Conclusions
A model-based dynamic classification approach had lower accuracy for ascertaining JA cases than a deterministic approach. However, the dynamic approach required a shorter duration of time to produce a case definition with acceptable PPV. The choice of methods to construct case definitions and their performance may depend on the characteristics of the chronic disease under investigation.
Methodology of the DCCSS later fatigue study: a model to investigate chronic fatigue in long-term survivors of childhood cancer
Authors: Penson Adriaan , van Deuren Sylvia , Bronkhorst Ewald , Keizer Ellen , Heskes Tom , Coenen Marieke J. H. , Rosmalen Judith G. M. , Tissing Wim J. E. , van der Pal Helena J. H. , de Vries Andrica C. H. , van den Heuvel-Eibrink Marry M. , Neggers Sebastian , Versluys Birgitta A. B. , Louwerens Marloes , van der Heiden-van der Loo Margriet , Pluijm Saskia M. F. , Grootenhuis Martha , Blijlevens Nicole , Kremer Leontien C. M. , van Dulmen-den Broeder Eline , Knoop Hans , Loonen Jacqueline 
Published: May 2021

Abstract
Background
A debilitating late effect for childhood cancer survivors (CCS) is cancer-related fatigue (CRF). Little is known about the prevalence and risk factors of fatigue in this population. Here we describe the methodology of the Dutch Childhood Cancer Survivor Late Effect Study on fatigue (DCCSS LATER fatigue study). The aim of the DCCSS LATER fatigue study is to examine the prevalence of and factors associated with CRF, proposing a model which discerns predisposing, triggering, maintaining and moderating factors. Triggering factors are related to the cancer diagnosis and treatment during childhood and are thought to trigger fatigue symptoms. Maintaining factors are daily life- and psychosocial factors which may perpetuate fatigue once triggered. Moderating factors might influence the way fatigue symptoms express in individuals. Predisposing factors already existed before the diagnosis, such as genetic factors, and are thought to increase the vulnerability to develop fatigue. Methodology of the participant inclusion, data collection and planned analyses of the DCCSS LATER fatigue study are presented.

Results
Data of 1955 CCS and 455 siblings was collected. Analysis of the data is planned and we aim to start reporting the first results in 2022.

Conclusion
The DCCSS LATER fatigue study will provide information on the epidemiology of CRF and investigate the role of a broad range of associated factors in CCS. Insight in associated factors for fatigue in survivors experiencing severe and persistent fatigue may help identify individuals at risk for developing CRF and may aid in the development of interventions.
Development and head-to-head comparison of machine-learning models to identify patients requiring prostate biopsy
Authors: Yu Shuanbao , Tao Jin , Dong Biao , Fan Yafeng , Du Haopeng , Deng Haotian , Cui Jinshan , Hong Guodong , Zhang Xuepei 
Published: May 2021

Abstract
Background
Machine learning has many attractive theoretic properties, specifically, the ability to handle non predefined relations. Additionally, studies have validated the clinical utility of mpMRI for the detection and localization of CSPCa (Gleason score ≥ 3 + 4). In this study, we sought to develop and compare machine-learning models incorporating mpMRI parameters with traditional logistic regression analysis for prediction of PCa (Gleason score ≥ 3 + 3) and CSPCa on initial biopsy.

Methods
A total of 688 patients with no prior prostate cancer diagnosis and tPSA ≤ 50 ng/ml, who underwent mpMRI and prostate biopsy were included between 2016 and 2020. We used four supervised machine-learning algorithms in a hypothesis-free manner to build models to predict PCa and CSPCa. The machine-learning models were compared to the logistic regression analysis using AUC, calibration plot, and decision curve analysis.

Results
The artificial neural network (ANN), support vector machine (SVM), and random forest (RF) yielded similar diagnostic accuracy with logistic regression, while classification and regression tree (CART, AUC = 0.834 and 0.867) had significantly lower diagnostic accuracy than logistic regression (AUC = 0.894 and 0.917) in prediction of PCa and CSPCa (all P < 0.05). However, the CART illustrated best calibration for PCa (SSR = 0.027) and CSPCa (SSR = 0.033). The ANN, SVM, RF, and LR for PCa had higher net benefit than CART across the threshold probabilities above 5%, and the five models for CSPCa displayed similar net benefit across the threshold probabilities below 40%. The RF (53% and 57%, respectively) and SVM (52% and 55%, respectively) for PCa and CSPCa spared more unnecessary biopsies than logistic regression (35% and 47%, respectively) at 95% sensitivity for detection of CSPCa.

Conclusion
Machine-learning models (SVM and RF) yielded similar diagnostic accuracy and net benefit, while spared more biopsies at 95% sensitivity for detection of CSPCa, compared with logistic regression. However, no method achieved desired performance. All methods should continue to be explored and used in complementary ways.
Training interns in nutrition and dietetics: a cross-sectional study of the barriers and motivators to being a Registered Dietitian Nutritionist preceptor
Authors: Hutchins Andrea M. , Winham Donna M. , Fellows Jinette P. , Heer Michelle M. 
Published: May 2021

Abstract
Background
As is common across the health professions, training of Registered Dietitian Nutritionists (RDNs) requires experiential learning for interns/students to gain skills and demonstrate entry-level competency. Preceptors are essential to the experiential learning component of health care professional training, providing supervision and mentoring as students and interns gain the skills required for entry-level practice competency. Over the past 27 years, 47–73% of applicants to dietetic internships have received a placement. Practitioners willing to volunteer as preceptors are needed to generate more internship or experiential learning opportunities for the profession to continue to meet workforce demands.

Methods
The objective of this national-level online cross-sectional survey was to identify perceptions and attitudes associated with the preceptor role and incentives that might encourage precepting by current RDNs. A random sample of RDN and Nutrition and Dietetic Technicians, Registered (NDTR) professionals from the Commission on Dietetic Registration credentialed practitioner database were eligible to participate in the online survey. The main outcome measures included perceptions, attitudes, and preferred incentives to precept compared by preceptor experience categories (current, former, never precepted). Comparisons of perceptions, attitudes, and preferred incentives were made between preceptor experience categories using Chi-square and ANOVA.

Results
Of 2464 invitations, 308 participants had complete variables for analysis. Top incentives were the opportunity to earn continuing education units (65.9%) and having expenses paid to attend a national conference (49.5%). Significantly more (P < 0.001) “former” and “never” preceptors reported the ability to choose when to take an intern, training on how to teach and communicate with interns, and access to an “on-call” specialist as incentives compared to “current” preceptors. Significantly more (P < 0.01) “never” preceptors reported training on internship expectations and the ability to provide input on intern selection process as incentives compared to “current” or “former” preceptors.

Conclusions
Incentives to serve as a preceptor differ based on “current”, “former”, or “never” precepted status. Promoting and strategizing solutions to the current imbalance between the greater number of dietetic internship applicants compared to preceptors should be targeted based on preceptor status to retain current preceptors, encourage former preceptors to return and recruit professionals who have never served.
The albumin-to-alkaline phosphatase ratio as an independent predictor of future non-alcoholic fatty liver disease in a 5-year longitudinal cohort study of a non-obese Chinese population
Authors: Sheng Guotai , Peng Nan , Hu Chong , Zhong Ling , Zhong Mingchun , Zou Yang 
Published: May 2021

Abstract
Background
The albumin-to-alkaline phosphatase ratio (AAPR) is a newly developed index of liver function, but its association in patients with non-alcoholic fatty liver disease (NAFLD) has not been established. The aim of this study was to investigate the association between the AAPR and NAFLD in a non-obese Chinese population.

Methods
The study included 10,749 non-obese subjects without NAFLD at baseline and divided them into quintiles according to the AAPR. A Cox multiple regression model was used to examine the association between the AAPR and its quintiles and the incidence of NAFLD.

Results
The average age of the study population was 43.65 ± 15.15 years old. During the 5-year follow-up, 1860 non-obese subjects had NAFLD events. In the Cox multiple regression model, after adjusting the model according to important risk factors, the AAPR and NAFLD risk were independently correlated, and with a gradual increase in the AAPR, the NAFLD risk decreased gradually (HR: 0.61, 95% CI: 0.47, 0.81; P-trend< 0.0001). Additionally, there were significant interactions between the AAPR and BMI, blood pressure and lipids (P-interaction < 0.05). Stratified analysis showed that the risk of AAPR-related NAFLD decreased in people with normal blood pressure and lipid levels, while the risk of AAPR-related NAFLD increased abnormally in people who were underweight.

Conclusions
This longitudinal cohort study provides the first evidence that the AAPR is an independent predictor of future NAFLD events in non-obese people. For non-obese people with a low AAPR, especially those with BMI < 18.5 kg/m2, more attention should be given to the management of risk factors for NAFLD to prevent future NAFLD.