bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outpatient healthcare costs associated with overweight and obesity in Italy
Authors: Atella Vincenzo , Belotti Federico , Cricelli Claudio , Giaccherini Matilde , Medea Gerardo , Nicolucci Antonio , Piano Mortari Andrea , Sbraccia Paolo 
Published: June 2023

Abstract
Background
To evaluate outpatient healthcare expenditure associated with different levels of BMI and glucose metabolism alterations.

Methods
The study is based on a representative national sample of adults, with data obtained from electronic clinical records of 900 Italian general practitioners. Data relative to the year 2018 were analyzed. The study population was classified according to BMI (normal weight, overweight, and obesity classes 1, 2, and 3) and glucose metabolism status (normoglycemia – NGT; impaired fasting glucose – IFG; diabetes mellitus – DM). Outpatient health expenditures include diagnostic tests, specialist visits, and drugs.

Results
Data relative to 991,917 adults were analyzed. Annual per capita expenditure rose from 252.2 Euro among individuals with normal weight to 752.9 Euro among those with class 3 obesity. The presence of obesity determined an excess cost, particularly among younger individuals. Within each BMI class, the presence of IFG or DM2 identified subgroups of individuals with substantially higher healthcare expenditures.

Conclusions
Outpatient healthcare costs markedly increased with increasing BMI in all age categories, particularly among individuals below 65. Addressing the double burden of excess weight and hyperglycemia represents a significant challenge and a healthcare priority.
Predictors of readmission in a medical department of a tertiary university hospital in the Philippines
Authors: Balane Janika Adrienne L. , Yap Celina Daia DG. , Villanueva Cary Amiel G. , Palileo-Villanueva Lia Aileen M. , Tamondong-Lachica Diana R. 
Published: June 2023

Abstract
Background
Identifying factors that increase the risk for hospital readmission helps in determining potential targets for quality improvement efforts. The main objective of this study was to examine factors that predict increased risk of hospital readmission within 30 days of hospital discharge of patients under the General Medicine service of a tertiary government hospital in Manila, Philippines.

Methods
We performed a retrospective cohort study which included service patients 19 years old and above readmitted within 30 days following discharge. A total of 324 hospital readmissions within 30 days of discharge from January 1 to December 31, 2019 were reviewed. We estimated the rate of 30-day readmission and identified factors associated with preventable readmissions using multivariable logistic regression.

Results
Of the 4,010 hospitalizations under General Medicine service in 2019, 602 (18%) were readmissions within 30 days of discharge, majority of which were related to the index admission (90%) and unplanned (68%). Predictors of preventable readmission were emergency readmission (OR 3.37, 95% CI 1.72 to 6.60), having five to ten medications at discharge (OR 1.78, 95% CI 1.10 to 2.87), and presence of nosocomial infection (OR 1.86, 95% CI 1.09 to 3.17). The most frequent reason for readmission among preventable ones is health-care related infection (42.9%).

Conclusions
We identified factors which increased the likelihood of preventable readmissions such as type of readmission, number of medications per day, and presence of nosocomial infections. We propose that these issues be addressed to improve healthcare delivery and reduce readmission-related expenditures. Further studies should be pursued to identify impactful evidence-based practices.
Novel compound heterozygous variants in the RPL3L gene causing dilated cardiomyopathy type-2D: a case report and literature review
Authors: Yang Qi , Zhang Qiang , Qin Zailong , Zhang Shujie , Yi Sheng , Yi Shang , Zhang Qinle , Luo Jingsi 
Published: June 2023

Abstract
Background
Dilated cardiomyopathy type-2D (CMD2D) is a rare heart disease causing a severe cardiomyopathy with neonatal onset and rapid progression to cardiac decompensation and death in untreated patients. CMD2D is an autosomal recessive disease resulting from variants in the RPL3L gene, which encodes the 60 S ribosomal protein exclusively expressed in skeletal and cardiac muscle and plays an essential role in myoblast growth and fusion. Previous reports have only associated CMD2D with a small duplication and seven nucleotide substitution in the RPL3L gene.

Case presentation
In this study, we report the case of a 31 days old Chinese infant patient with severe dilated cardiomyopathy (DCM) and rapid decompensation along with other cardiac malformations. In addition to previously reported clinical features, the patient showed the previously unreported complication of occasional premature atrial contractions and a first-degree atrioventricular block. Whole-exome sequencing (WES) revealed compound heterozygous variants (c.80G > A (p.Gly27Asp) and c.1074dupA (p.Ala359fs*6)) in RPL3L (NM_005061.3). The latter novel variant may result in the absence of protein production with a significant decrease in mRNA level, suggesting it is a loss-of-function mutation.

Conclusions
This is the first case report of RPL3L-associated neonatal dilated cardiomyopathy in China. The molecular confirmation of the patient expands the genetic spectrum of CMD2D, and the clinical manifestation of CMD2D in the patient provides additional clinical information regarding this disease.
Flavonoids target different molecules of autophagic and metastatic pathways in cancer cells
Authors: Hosseinzadeh Aysooda , Poursoleiman Faezeh , Biregani Akram Naghdipour , Esmailzadeh Ahmad 
Published: June 2023

AbstractDespite the success of cancer therapy, it has encountered a major obstacle due to the complicated nature of cancer, namely resistance. The recurrence and metastasis of cancer occur when anti-cancer therapeutic agents fail to eradicate all cancer cells. Cancer therapy aims to find the best agent that targets all cancer cells, including those sensitive or resistant to treatment. Flavonoids, natural products from our diet, show anti-cancer effects in different studies. They can inhibit metastasis and the recurrence of cancers. This review discusses metastasis, autophagy, anoikis in cancer cells, and their dynamic relationship. We present evidence that flavonoids can block metastasis and induce cell death in cancer cells. Our research suggests that flavonoids can serve as potential therapeutic agents in cancer therapy.
HNRNPA2B1-mediated m6A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis
Authors: Li Ke , Gong Quan , Xiang Xu-Dong , Guo Gang , Liu Jia , Zhao Li , Li Jun , Chen Nan , Li Heng , Zhang Li-Juan , Zhou Chun-Yan , Wang Zhi-Yong , Zhuang Li 
Published: June 2023

Abstract
Background
Accumulating data indicate that N6-methyladenosine (m6A) RNA methylation and lncRNA deregulation act crucial roles in cancer progression. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as an m6A “reader” has been reported to be an oncogene in multiple malignancies. We herein aimed to elucidate the role and underlying mechanism by which HNRNPA2B1-mediated m6A modification of lncRNAs contributes to non-small cell lung cancer (NSCLC).

Methods
The expression levels of HNRNPA2B1 and their association with the clinicopathological characteristics and prognosis in NSCLC were determined by RT-qPCR, Western blot, immunohistochemistry and TCGA dataset. Then, the role of HNRNPA2B1 in NSCLC cells was assessed by in vitro functional experiments and in vivo tumorigenesis and lung metastasis models. HNRNPA2B1-mediated m6A modification of lncRNAs was screened by m6A-lncRNA epi-transcriptomic microarray and verified by methylated RNA immunoprecipitation (Me-RIP). The lncRNA MEG3-specific binding with miR-21-5p was evaluated by luciferase gene report and RIP assays. The effects of HNRNPA2B1 and (or) lncRNA MEG3 on miR-21-5p/PTEN/PI3K/AKT signaling were examined by RT-qPCR and Western blot analyses.

Results
We found that upregulation of HNRNPA2B1 was associated with distant metastasis and poor survival, representing an independent prognostic factor in patients with NSCLC. Knockdown of HNRNPA2B1 impaired cell proliferation and metastasis in vitro and in vivo, whereas ectopic expression of HNRNPA2B1 possessed the opposite effects. Mechanical investigations revealed that lncRNA MEG3 was an m6A target of HNRNPA2B1 and inhibition of HNRNPA2B1 decreased MEG3 m6A levels but increased its mRNA levels. Furthermore, lncRNA MEG3 could act as a sponge of miR-21-5p to upregulate PTEN and inactivate PI3K/AKT signaling, leading to the suppression of cell proliferation and invasion. Low expression of lncRNA MEG3 or elevated expression of miR-21-5p indicated poor survival in patients with NSCLC.

Conclusions
Our findings uncover that HNRNPA2B1-mediated m6A modification of lncRNA MEG3 promotes tumorigenesis and metastasis of NSCLC cells by regulating miR-21-5p/PTEN axis and may provide a therapeutic target for NSCLC.
Varicella-zoster virus proteome-wide T-cell screening demonstrates low prevalence of virus-specific CD8 T-cells in latently infected human trigeminal ganglia
Authors: van Gent Michiel , Ouwendijk Werner J. D. , Campbell Victoria L. , Laing Kerry J. , Verjans Georges M. G. M. , Koelle David M. 
Published: June 2023

Abstract
Background
Trigeminal ganglia (TG) neurons are an important site of lifelong latent varicella-zoster virus (VZV) infection. Although VZV-specific T-cells are considered pivotal to control virus reactivation, their protective role at the site of latency remains uncharacterized.

Methods
Paired blood and TG specimens were obtained from ten latent VZV-infected adults, of which nine were co-infected with herpes simplex virus type 1 (HSV-1). Short-term TG-derived T-cell lines (TG-TCL), generated by mitogenic stimulation of TG-derived T-cells, were probed for HSV-1- and VZV-specific T-cells using flow cytometry. We also performed VZV proteome-wide screening of TG-TCL to determine the fine antigenic specificity of VZV reactive T-cells. Finally, the relationship between T-cells and latent HSV-1 and VZV infections in TG was analyzed by reverse transcription quantitative PCR (RT-qPCR) and in situ analysis for T-cell proteins and latent viral transcripts.

Results
VZV proteome-wide analysis of ten TG-TCL identified two VZV antigens recognized by CD8 T-cells in two separate subjects. The first was an HSV-1/VZV cross-reactive CD8 T-cell epitope, whereas the second TG harbored CD8 T-cells reactive with VZV specifically and not the homologous peptide in HSV-1. In silico analysis showed that HSV-1/VZV cross reactivity of TG-derived CD8 T-cells reactive with ten previously identified HSV-1 epitopes was unlikely, suggesting that HSV-1/VZV cross-reactive T-cells are not a common feature in dually infected TG. Finally, no association was detected between T-cell infiltration and VZV latency transcript abundance in TG by RT-qPCR or in situ analyses.

Conclusions
The low presence of VZV- compared to HSV-1-specific CD8 T-cells in human TG suggests that VZV reactive CD8 T-cells play a limited role in maintaining VZV latency.
Chinese genetic variation database of inborn errors of metabolism: a systematic review of published variants in 13 genes
Authors: Guo Yongchao , Jiang Jianhui , Xu Zhongyao 
Published: June 2023

Abstract
Background
Population-specific variation database of inborn errors of metabolism (IEMs) is essential for precise genetic diagnosis and disease prevention. Here we presented a systematic review of clinically relevant variants of 13 IEMs genes reported among Chinese patients.

Methods
A systematic search of the following electronic databases for 13 IEMs genes was conducted: PubMed-NCBI, China national knowledge infrastructure and Wanfang databases. Patient data was extracted from articles eligible for inclusion and recorded in Excel electronic form using a case-by-case approach.

Results
A total of 218 articles, 93 published in English and 125 in Chinese, were retrieved. After variant annotation and deduplication, 575 unique patients (241 from articles published in Chinese) were included in the population-specific variation database. Patients identified by newborn screening and symptomatic presentation were 231 (40.17%) and 344 (59.83%), respectively. Biallelic variants were observed in 525/575 (91.3%). Among the 581 unique variants identified, 83 (14.28%) were described ≥ 3 times and 97 (16.69%) were not recorded in Clinvar or HGMD. Four variants were reclassified as benign and dozens of confusing variants deserved further research.

Conclusion
This review provides a unique resource of the well-characterized diseases and causative variants that have accumulated in Chinese population and is a preliminary attempt to build the Chinese genetic variation database of IEMs.
Expanding genotype–phenotype correlations in FOXG1 syndrome: results from a patient registry
Authors: Brimble Elise , Reyes Kathryn G. , Kuhathaas Kopika , Devinsky Orrin , Ruzhnikov Maura R. Z. , Ortiz-Gonzalez Xilma R. , Scheffer Ingrid , Bahi-Buisson Nadia , Olson Heather ,   the FOXG1 Research Foundation
Published: June 2023

Abstract
Background
We refine the clinical spectrum of FOXG1 syndrome and expand genotype–phenotype correlations through evaluation of 122 individuals enrolled in an international patient registry.

Methods
The FOXG1 syndrome online patient registry allows for remote collection of caregiver-reported outcomes. Inclusion required documentation of a (likely) pathogenic variant in FOXG1. Caregivers were administered a questionnaire to evaluate clinical severity of core features of FOXG1 syndrome. Genotype–phenotype correlations were determined using nonparametric analyses.

Results
We studied 122 registry participants with FOXG1 syndrome, aged < 12 months to 24 years. Caregivers described delayed or absent developmental milestone attainment, seizures (61%), and movement disorders (58%). Participants harbouring a missense variant had a milder phenotype. Compared to individuals with gene deletions (0%) or nonsense variants (20%), missense variants were associated with more frequent attainment of sitting (73%). Further, individuals with missense variants (41%) achieved independent walking more frequently than those with gene deletions (0%) or frameshift variants (6%). Presence of epilepsy also varied by genotype and was significantly more common in those with gene deletions (81%) compared to missense variants (47%). Individuals with gene deletions were more likely to have higher seizure burden than other genotypes with 53% reporting daily seizures, even at best control. We also observed that truncations preserving the forkhead DNA binding domain were associated with better developmental outcomes.

Conclusion
We refine the phenotypic spectrum of neurodevelopmental features associated with FOXG1 syndrome. We strengthen genotype-driven outcomes, where missense variants are associated with a milder clinical course.
Oral findings in patients with cartilage-hair hypoplasia - cross-sectional observational study
Authors: Arponen Heidi , Vakkilainen Svetlana , Rautava Jaana , Mäkitie Outi 
Published: June 2023

Abstract
Background and objectives
Cartilage-hair hypoplasia (CHH) is a rare chondrodysplasia with associated primary immunodeficiency. The aim of this cross-sectional study was to examine oral health indicators in individuals with CHH.

Methods
In total, 23 individuals with CHH, aged between 4.5 and 70 years, and 46 controls aged between 5 and 76 years were clinically examined for periodontal disease, presence of oral mucosal lesions, tooth decay, masticatory system function, and malocclusions. A chairside lateral flow immunoassay test of active-matrix metalloproteinase was obtained from all the adult participants with a permanent dentition. Laboratory signs of immunodeficiency were recorded for individuals with CHH.

Results
Individuals with CHH and controls had similar prevalence of gingival bleeding on probing (median 6% vs. 4%). Oral fluid active-matrix metalloproteinase concentration was greater than 20 ng/ml in 45% of study subjects in both groups. However, deep periodontal pockets, 4 mm or deeper, were more common in individuals with CHH as compared to the controls (U = 282.5, p = 0.002). Similarly mucosal lesions were significantly more common in individuals with CHH (30% vs. 9%, OR = 0.223, 95%CI 0.057–0.867). The median sum of the number of decayed, missing due to caries, and filled teeth was nine for the individuals with CHH and four for controls. In the CHH cohort, 70% displayed an ideal sagittal occlusal relationship. Malocclusion and temporomandibular joint dysfunction prevalence were similar in both study groups.

Conclusions
Individuals with CHH have more frequently deep periodontal pockets and oral mucosal lesions than general population controls. Routine intraoral examination by a dentist at regular intervals should be recommended to all individuals with CHH.
Patients, payers and developers of Orphan Medicinal Products: lessons learned from 10 years’ multi-stakeholder dialogue on improving access in Europe via MoCA
Authors: Cavaller-Bellaubi Maria , Hughes-Wilson Wills , Kubinová Šárka , Van de Casteele Marc , Van Lente Evert Jan , Degortes Emanuele , Pontén Johan , Eichler Hans-Georg , Le Cam Yann , Boselli Simone , Bucsics Anna 
Published: June 2023

Abstract
Background
The Mechanism of Coordinated Access to Orphan Medicinal Products (MoCA) was established in 2013 with the intention of developing a coordinated mechanism between volunteering EU stakeholders and developers of Orphan Medicinal Products (OMPs) to support the exchange of information aimed at enabling informed decisions on pricing and reimbursement at Member State level and to evaluate the value of an OMP based on a Transparent Value Framework. The objective of the collaborative approach was to support more equitable access to authorised therapies for people living with rare diseases, rational prices for payers and more predictable market conditions for OMP developers. Over the past 10 years, the MoCA has conducted a series of pilot projects, examining a variety of different products and technologies at different stages of development; and with contributions from a variety of patient representatives, participation from EU payers from a range of Member States and, recently, with EUnetHTA members and the European Medicines Agency participating in the meetings as observers.

Results
10 years on from the establishment of the MoCA, the European landscape has significantly evolved, not only in the field of drug development with increasingly transformative therapies based on novel technologies, but also in terms of larger numbers of approved treatments, increased budget impact and the resulting associated uncertainties; as well as in terms of stakeholder collaboration and interactions. The value of early dialogue with OMP developers, including the EU payer community via their national decision-making authorities, is a key element within this early interaction and contributes to identifying, managing and reducing uncertainties allowing a prospectively planned approach earlier in development and, consequently, to support more timely, sustainable and equitable access to new OMPs, particularly where there is a high unmet medical need.

Conclusions
The voluntary, informal nature of the MoCA interactions creates a flexible framework for non-binding dialogue. A forum for such interactions is needed to achieve the aims of the MoCA and both to support healthcare systems in planning as well as to underpin timely, equitable and sustainable access to new therapies for patients with rare diseases within the EU.
Quality of life and physical/psychosocial factors in children and adolescents with orthostatic intolerance
Authors: Shigeyasu Yoshie , Okada Ayumi , Fujii Chikako , Tanaka Chie , Sugihara Akiko , Horiuchi Makiko , Yorifuji Takashi , Tsukahara Hirokazu 
Published: June 2023

Abstract
Background
Orthostatic intolerance (OI), which is common in children and adolescents, negatively impacts their quality of life (QOL) due to physical symptoms that limit work, school, and daily activities. The purpose of this study is to explore the association of physical and psychosocial factors with QOL scores in children and adolescents with OI.

Methods
A cross sectional observational study was conducted. The study participants included 95 Japanese pediatric patients of age 9–15 years who were diagnosed with OI from April 2010 to March 2020. The QOL scores and the QOL T-scores of children with OI assessed using the KINDL-R questionnaire at the initial visit were compared with conventional normative data. The associations of physical and psychosocial factors with the QOL T-scores were examined using multiple linear regression.

Results
Pediatric patients with OI had significantly lower QOL scores than healthy children in both elementary (50.7 ± 13.5 vs. 67.9 ± 13.4, p < 0.001) and junior high schools (51.8 ± 14.6 vs. 61.3 ± 12.6, p < 0.001). This finding was observed in the physical, mental, self-esteem, friends, and school domains. Total QOL scores were significantly associated with school nonattendance (β =  − 3.2, 95% confidence interval [CI] =  − 5.8 to − 0.5, p = 0.022) and poor relationship with school (β =  − 5.0, 95% CI =  − 9.8 to − 0.4, p = 0.035).

Conclusions
These results suggest that the assessment of QOL, including both physical and psychosocial aspects, especially school factors, needs to be implemented earlier in children and adolescents with OI.
Firm performance over innovation cycle: evidence from a small European economy
Authors: Baláž Vladimír , Jeck Tomáš , Balog Miroslav 
Published: June 2023

AbstractInnovation is seen as a key capability for maintaining competitive advantage, creating value for customers, and capturing a larger share of the market. Yet, empirical evidence on the impact of innovation on firm performance is mixed. This research adds to the current debate on the relationship between innovation and the economic performance of firms. It brings new evidence from a small European economy (i.e., the Slovak Republic). We use a unique data set on 170 firms supported by the European Structural and Cohesion Funds (ESCF). Actual economic data reported in companies’ annual accounts, rather than self-reported information, is used to follow firm performance over a longer term horizon. The most significant finding is that the company’s innovation strategy was a key mediator of capability development and, ultimately, economic performance. The importance of specific innovation strategies varied over the innovation cycle. Simple process and organisational innovations were perceived to be important when assessing the immediate effects of European assistance. Investment in and cooperation on R&D&I became important when assessing firm performance over the longer term. The research expands the current body of literature on innovation capabilities and economic performance. It accentuates the need for a long-term perspective on innovation capabilities. To maintain a competitive advantage, a company's innovation capabilities must be constantly aligned with the changing environment.