bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does de-implementation of low-value care impact the patient-clinician relationship? A mixed methods study
Authors: Rockwell Michelle S. , Michaels Kenan C. , Epling John W. 
Published: January 2022

AbstractBackgroundThe importance of reducing low-value care (LVC) is increasingly recognized, but the impact of de-implementation on the patient-clinician relationship is not well understood. This mixed-methods study explored the impact of LVC de-implementation on the patient-clinician relationship.MethodsAdult primary care patients from a large Virginia health system volunteered to participate in a survey (n = 232) or interview (n= 24). Participants completed the Patient-Doctor Relationship Questionnaire (PDRQ-9) after reading a vignette about a clinician declining to provide a low-value service: antibiotics for acute sinusitis (LVC-antibiotics); screening EKG (LVC-EKG); screening vitamin D test (LVC-vitamin D); or an alternate vignette about a high-value service, and imagining that their own primary care clinician had acted in the same manner. A different sample of participants was asked to imagine that their own primary care clinician did not order LVC-antibiotics or LVC-EKG and then respond to semi-structured interview questions. Outcomes data included participant demographics, PDRQ-9 scores (higher score = greater relationship integrity), and content analysis of transcribed interviews. Differences in PDRQ-9 scores were analyzed using one-way ANOVA. Data were integrated for analysis and interpretation.ResultsAlthough participants generally agreed with the vignette narrative (not providing LVC), many demonstrated difficulty comprehending the broad concept of LVC and potential harms. The topic triggered memories of negative experiences with healthcare (typically poor-quality care, not necessarily LVC). The most common recommendation for reducing LVC was for patients to take greater responsibility for their own health. Most participants believed that their relationship with their clinician would not be negatively impacted by denial of LVC because they trusted their clinician’s guidance. Participants emphasized that trusted clinicians are those who listen to them, spend time with them, and offer understandable advice. Some felt that not providing LVC would actually increase their trust in their clinician. Similar PDRQ-9 scores were observed for LVC-antibiotics (38.9), LVC-EKG (37.5), and the alternate vignette (36.4), but LVC-vitamin D was associated with a significantly lower score (31.2) (p < 0.05).ConclusionsIn this vignette-based study, we observed minimal impact of LVC de-implementation on the patient-clinician relationship, although service-specific differences surfaced. Further situation-based research is needed to confirm study findings.
Molecular characterization and phylogenetic analysis of bovine ephemeral fever viruses in Khuzestan province of Iran in 2018 and 2020
Authors: Rezatofighi Seyedeh Elham , Mirzadeh Khalil , Mahmoodi Fahimeh 
Published: January 2022

AbstractBackgroundBovine ephemeral fever (BEF) is an arthropod-borne viral disease caused by the BEF virus (BEFV). This single-stranded RNA virus that affects cattle and water buffalo is endemic in tropical and subtropical regions including Iran. While BEF is a major disease of cattle in Iran, information regarding its agent, molecular characterization, and circulating viruses are highly limited. The current study aimed to, firstly, determine the genetic and antigenic characteristics of BEFV strains in Khuzestan province in Southwest of Iran in 2018 and 2020 and, secondly, to compare them with strains obtained from other areas.ResultsBy phylogenetic analysis based on the Glycoprotein gene, BEFV strains were divided into four clusters of Middle East, East Asia, South Africa, and Australia; in which the 2018 and 2020 Iranian BEFV strains were grouped in the Middle East cluster with the Turkish, Indian, and Israeli strains. Depending on the chronology and geographical area, the outbreaks of Turkey (2020), Iran (2018 and 2020), and India (2018 and 2019) are proposed to be related. These BEFVs had the highest identity matrix and the lowest evolutionary distance among the studied strains. Multiple sequence alignment of G1, G2, and G3 antigenic sites showed that these neutralizing epitopes are highly conserved among the strains of the Middle East cluster; however, the strains previously identified in Iran differed in three amino acids placed in G1 and G2 epitopes.ConclusionThe findings revealed that BEFVs circulating in the Middle East are closely related phylogenetically and geographically. They also have similar antigenic structures; therefore, developing a vaccine based on these strains can be effective for controlling BEF in the Middle East.
Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers
Authors: Gessner Arne , Gemeinhardt Anna , Bosch Agnes , Kannenkeril Dennis , Staerk Christian , Mayr Andreas , Fromm Martin F. , Schmieder Roland E. , Maas Renke 
Published: January 2022

AbstractBackgroundIn patients with type 2 diabetes (T2D) sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemic control as well as cardiovascular and renal outcomes. Their effects onl-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported.MethodsPlasma and 24-h urine samples taken before and after 6 weeks of treatment were available from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with empagliflozin (71 patients analyzed, NCT02471963) and dapagliflozin (59 patients analyzed, NCT02383238). In these samples, concentrations of hArg, Arg, ADMA, SDMA, and creatinine were determined by liquid-chromatography coupled to tandem mass-spectrometry. Additionally, intraindividual changes of the biomarkers in plasma were correlated with intraindividual changes of clinical parameters.ResultsTreatment with empagliflozin and dapagliflozin was associated with a reduction of plasma hArg by 17.5% and 13.7% (both p < 0.001), respectively, and increase in plasma SDMA concentration of 6.7% and 3.6%, respectively (p < 0.001 and p < 0.05), while plasma Arg and ADMA concentrations were not significantly altered. 24-h urinary excretion of ADMA was reduced by 15.2% after treatment with empagliflozin (p < 0.001) but not after dapagliflozin treatment, while excretion of the other markers was not significantly altered. Renal clearance of SDMA was reduced by 9.1% and 3.9% for both drugs (both p < 0.05). A reduction in ADMA clearance was observable after empagliflozin treatment only (− 15.5%, p < 0.001), but not after dapagliflozin. Renal clearance of hArg and Arg was not significantly altered. Treatment effects onl-arginine related biomarkers were not constantly correlated with effects on glycated hemoglobin, fasting plasma glucose, body mass index, and systolic blood pressure.ConclusionsTreatment with SGLT-2 inhibitors has divergent effects on Arg-related biomarkers and could affect risk estimates associated with these markers. The observed effects are unlikely to explain the known cardiovascular and renal benefits of treatment with empagliflozin or dapagliflozin but still may indicate new therapeutic approaches in patients treated with SGLT-2 inhibitors.Trial registrationhttp://www.clinicaltrials.gov: NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.
PHD finger protein 20-like protein 1 (PHF20L1) in ovarian cancer: from its overexpression in tissue to its upregulation by the ascites microenvironment
Authors: Alberto-Aguilar Dulce Rosario , Hernández-Ramírez Verónica Ivonne , Osorio-Trujillo Juan Carlos , Gallardo-Rincón Dolores , Toledo-Leyva Alfredo , Talamás-Rohana Patricia 
Published: January 2022

Abstract
Background
Ovarian cancer is the most aggressive gynecological malignancy. Transcriptional regulators impact the tumor phenotype and, consequently, clinical progression and response to therapy. PHD finger protein 20-like protein 1 (PHF20L1) is a transcriptional regulator with several isoforms, and studies on its role in ovarian cancer are limited. We previously reported that PHF20L1 is expressed as a fucosylated protein in SKOV-3 cells stimulated with ascites from patients with ovarian cancer.

Methods
We decided to analyze the expression of PHF20L1 in ovarian cancer tissues, determine whether a correlation exists between PHF20L1 expression and patient clinical data, and analyze whether ascites can modulate the different isoforms of this protein. Ovarian cancer biopsies from 29 different patients were analyzed by immunohistochemistry, and the expression of the isoforms in ovarian cancer cells with or without exposure to the tumor microenvironment, i.e., the ascitic fluid, was determined by western blotting assays.

Results
Immunohistochemical results suggest that PHF20L1 exhibits increased expression in sections of tumor tissues from patients with ovarian cancer and that higher PHF20L1 expression correlates with shorter progression-free survival and shorter overall survival. Furthermore, western blotting assays determined that protein isoforms are differentially regulated in SKOV-3 cells in response to stimulation with ascites from patients with epithelial ovarian cancer.

Conclusion
The results suggest that PHF20L1 could play a relevant role in ovarian cancer given that higher PHF20L1 protein expression is associated with lower overall patient survival.
Annexin A1 promotes the progression of bladder cancer via regulating EGFR signaling pathway
Authors: Li Piao , Li Lingling , Li Zhou , Wang Shennan , Li Ruichao , Zhao Weiheng , Feng Yanqi , Huang Shanshan , Li Lu , Qiu Hong , Xia Shu 
Published: January 2022

Abstract
Background
Bladder cancer (BLCA) is one of the most common malignancies worldwide. One of the main reasons for the unsatisfactory management of BLCA is the complex molecular biological mechanism. Annexin A1 (ANXA1), a Ca2+-regulated phospholipid-binding protein, has been demonstrated to be implicated in the progression and prognosis of many cancers. However, the expression pattern, biological function and mechanism of ANXA1 in BLCA remain unclear.

Methods
The clinical relevance of ANXA1 in BLCA was investigated by bioinformatics analysis based on TCGA and GEO datasets. Immunohistochemical (IHC) analysis was performed to detect the expression of ANXA1 in BLCA tissues, and the relationships between ANXA1 and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to study the biological functions of ANXA1 in BLCA. Finally, the potential mechanism of ANXA1 in BLCA was explored by bioinformatics analysis and verified by in vitro and in vivo experiments.

Results
Bioinformatics and IHC analyses indicated that a high expression level of ANXA1 was strongly associated with the progression and poor prognosis of patients with BLCA. Functional studies demonstrated that ANXA1 silencing inhibited the proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of BLCA cells in vitro, and suppressed the growth of xenografted bladder tumors in vivo. Mechanistically, loss of ANXA1 decreased the expression and phosphorylation level of EGFR and the activation of downstream signaling pathways. In addition, knockdown of ANXA1 accelerated ubiquitination and degradation of P-EGFR to downregulate the activation of EGFR signaling.

Conclusions
These findings indicate that ANXA1 is a reliable clinical predictor for the prognosis of BLCA and promotes proliferation and migration by activating EGFR signaling in BLCA. Therefore, ANXA1 may be a promising biomarker for the prognosis of patients with BLCA, thus shedding light on precise and personalized therapy for BLCA in the future.
Systematic analysis of the role of SLC52A2 in multiple human cancers
Authors: Zhang Lilong , Li Man , Cui Zhoujun , Chai Dongqi , Guan Yongjun , Chen Chen , Wang Weixing 
Published: January 2022

Abstract
Background
In humans, riboflavin must be obtained through intestinal absorption because it cannot be synthesized by the body. SLC52A2 encodes a membrane protein belonging to the riboflavin transporter protein family and is associated with a variety of diseases. Here, we systematically explore its relevance to multiple human tumors.

Methods
We analyzed the association of SLC52A2 with 33 tumors using publicly available databases such as TCGA and GEO. We verified the SLC52A2 expression in hepatocellular carcinoma, gastric cancer, colon cancer, and rectal cancer using immunohistochemistry.

Results
We report that SLC52A2 was highly expressed in almost all tumors, and the immunohistochemical results in the hepatocellular, gastric, colon, and rectal cancers were consistent with the above. SLC52A2 expression was linked to patient overall survival, disease-specific survival, progression-free interval, diagnosis, mutations, tumor mutational burden, microsatellite instability, common immune checkpoint genes, and immune cells infiltration. Enrichment analysis showed that SLC52A2 was mainly enriched in oocyte meiosis, eukaryotic ribosome biogenesis, and cell cycle. In hepatocellular carcinoma, the SLC52A2 expression is an independent prognostic factor. The SNHG3 and THUMPD3-AS1/hsa-miR-139-5p-SLC52A2 axis were identified as potential regulatory pathways in hepatocellular carcinoma.

Conclusion
In conclusion, we have systematically described for the first time that SLC52A2 is closely associated with a variety of tumors, especially hepatocellular carcinoma.
Hydrogel composite scaffolds achieve recruitment and chondrogenesis in cartilage tissue engineering applications
Authors: Huang Bo , Li Pinxue , Chen Mingxue , Peng Liqing , Luo Xujiang , Tian Guangzhao , Wang Hao , Wu Liping , Tian Qinyu , Li Huo , Yang Yu , Jiang Shuangpeng , Yang Zhen , Zha Kangkang , Sui Xiang , Liu Shuyun , Guo Quanyi 
Published: January 2022

Abstract
Background
The regeneration and repair of articular cartilage remains a major challenge for clinicians and scientists due to the poor intrinsic healing of this tissue. Since cartilage injuries are often clinically irregular, tissue-engineered scaffolds that can be easily molded to fill cartilage defects of any shape that fit tightly into the host cartilage are needed.

Method
In this study, bone marrow mesenchymal stem cell (BMSC) affinity peptide sequence PFSSTKT (PFS)-modified chondrocyte extracellular matrix (ECM) particles combined with GelMA hydrogel were constructed.

Results
In vitro experiments showed that the pore size and porosity of the solid-supported composite scaffolds were appropriate and that the scaffolds provided a three-dimensional microenvironment supporting cell adhesion, proliferation and chondrogenic differentiation. In vitro experiments also showed that GelMA/ECM-PFS could regulate the migration of rabbit BMSCs. Two weeks after implantation in vivo, the GelMA/ECM-PFS functional scaffold system promoted the recruitment of endogenous mesenchymal stem cells from the defect site. GelMA/ECM-PFS achieved successful hyaline cartilage repair in rabbits in vivo, while the control treatment mostly resulted in fibrous tissue repair.

Conclusion
This combination of endogenous cell recruitment and chondrogenesis is an ideal strategy for repairing irregular cartilage defects.

Graphical Abstract
CRISPR/Cas9 delivery by NIR-responsive biomimetic nanoparticles for targeted HBV therapy
Authors: Wang Dan , Chen Ling , Li Chengbi , Long Quanxin , Yang Qing , Huang Ailong , Tang Hua 
Published: January 2022

Abstract
Background
Currently, there are no curative drugs for hepatitis B virus (HBV). Complete elimination of HBV covalently closed circular DNA (cccDNA) is key to the complete cure of hepatitis B virus infection. The CRISPR/Cas9 system can directly destroy HBV cccDNA. However, a CRISPR/Cas9 delivery system with low immunogenicity and high efficiency has not yet been established. Moreover, effective implementation of precise remote spatiotemporal operations in CRISPR/Cas9 is a major limitation.

Results
In this work, we designed NIR-responsive biomimetic nanoparticles (UCNPs-Cas9@CM), which could effectively deliver Cas9 RNP to achieve effective genome editing for HBV therapy. HBsAg, HBeAg, HBV pgRNA and HBV DNA along with cccDNA in HBV-infected cells were found to be inhibited. These findings were confirmed in HBV-Tg mice, which did not exhibit significant cytotoxicity and minimal off-target DNA damage.

Conclusions
The UCNPs-based biomimetic nanoplatforms achieved the inhibition of HBV replication via CRISPR therapy and it is a potential system for efficient treatment of human HBV diseases.

Graphical Abstract
Stress, pain, and work affiliation are strongly associated with health-related quality of life in parents of 14–15-year-old adolescents
Authors: Rohde Gudrun , Helseth Sølvi , Mikkelsen Hilde Timenes , Skarstein Siv , Småstuen Milada Cvancarova , Haraldstad Kristin 
Published: January 2022

Abstract
Background
For many adults, their role as a parent is a vital part of their lives. This role is likely to be associated with a parent’s health-related quality of life (HRQOL). The aim of this study was to explore the associations between gender, demographic and psychosocial variables, pain, and HRQOL in parents of 14–15-year-old adolescents.

Methods
This was a cross-sectional study that included 561 parents. Data on demographic, psychosocial variables and pain were collected using validated instruments. HRQOL was assessed using the RAND-36. Data were analysed using univariate and hierarchical multiple linear regression analyses.

Results
Four hundred and thirty-six (78%) mothers and 125 (22%) fathers with a mean age of 45 (SD = 5) years were included. Eighty-one per cent were married/cohabiting, 74% worked full time, and 50% had university education of more than 4 years. Almost one-third reported daily or weekly pain, and more than half (58%) reported using pain analgesics during the previous 4 weeks. Mothers reported significantly lower scores on self-efficacy, self-esteem and for all RAND-36 domains, including the physical component summary (PCS) and mental component summary (MCS) and experienced greater stress than fathers. Hierarchical regression analyses showed that working part-time (beta = 0.40) or full time (beta = 0.52) (reference: not working) had the strongest positive effect on PCS. Absence from work for > 10 days (beta = −0.24) (reference: no absence), short-term pain (beta = −0.14), chronic pain (beta = −0.37) (reference: no pain), and stress (beta = −0.10) had the strongest negative effects on PCS. High self-esteem (beta = 0.11) had the strongest positive effect, whereas stress (beta = −0.58) and absence from work for > 10 days (beta = −0.11) (reference: no absence) had the strongest negative effects on MCS.

Conclusion
Mothers reported significantly lower scores on self-efficacy, self-esteem, and HRQOL, and experienced greater stress than the fathers. A high proportion of parents reported pain. Pain, stress, and low work affiliation were strongly associated with decreased HRQOL in parents. We recommend that parents of adolescents should be provided guidance about coping with pain and stress, and facilitation of a strong work affiliation because these seem to be important to parents’ HRQOL.
Three decades of a lesson learned from Thailand: compulsory service for dentist workforce distribution
Authors: Arunratanothai Tanit , Booncharoen Ravisorn , Suwankomolkul Sirapop , Limpuangthip Nareudee 
Published: January 2022

Abstract
Background
Thailand has encountered an imbalanced dentist distribution and an internal brain drain of dentists from public to private health care facilities. To tackle these challenges, the compulsory service (CS) program, which has been initially implemented for physicians, was extended for dentists.

Method
This policy and workforce document review describes the background, development, and policy implementation of the CS program in Thailand during the past three decades. Outcomes after policy implementation and future directions are also discussed. The information was gathered from the relevant policy and workforce documents available from 1961 to 2021.

Results
In Thailand, junior dentists, specifically newly graduates, have to enroll in the CS program by working as oral health practitioners in public hospitals for at least 3 years. Dentists must pay a maximum fine of 400 000 baht (~ 12 571 USD) if they wish to skip the program. This fine is lowered according to the number of attending years in the program. CS program conditions are related to each university’s admission track. The CS enrolled dentists receive several financial and non-financial benefits, including educational, employment-related, and living provisions. Altogether, successive Thai governments have launched directive policies to increase dentist distribution in rural areas and their retention in public hospitals. These policies have been implemented in 3 stages: (1) increase production of new dentists, (2) allocation of newly dental graduates to public hospitals, and (3) provide benefits for working in public hospitals.

Conclusion
During the past three decades, several public policies have been implemented to improve dentist retention and distribution to public hospitals across Thailand, particularly in rural areas. The present CS program may not completely resolve the oral health inequalities because the dentist retention rate in public hospitals depends on multi-dimensional considerations. Further modifications on the CS program and future well-planned policies are needed.
Longitudinal study of the impact of three major regulations on the Korean pharmaceutical industry in the last 30 years
Authors: Um Seung In , Sohn Uy Dong , Jung Sun-Young , You Seung-Hun , Kim Changone , Lee Sora , Lee Heesang 
Published: January 2022

Abstract
Background
The pharmaceutical industry is heavily regulated. Partly for this reason, new drugs generally take over 10 years from the product development stage to market entry. Although regulations affect the pharmaceutical industry over a long period, previous studies investigating the impact of new regulatory policies have usually focused on the short period before and after implementing that policy. Therefore, the purpose of this study is to examine whether and how significantly regulatory policies affect long-term innovation in the pharmaceutical industry in Korea.

Methods
This study focused on three significant regulatory policies: the introduction of the product patent system, changes in the Good Manufacturing Practice (GMP) system, and the Drug Expenditure Rationalization Plan (DERP). The study used interrupted time series (ITS) analysis to investigate the long-term impacts of the policies before and after implementation.

Results
Our results show that introducing the product patent system in 1987 significantly increased the number of Korean patent applications. The effect of the revised GMP policies was also statistically significant, both before and after implementation and between pre-emptive companies and non-pre-emptive ones. However, due to the companies' negotiations with the regulatory authorities or the regulatory system that links drug approval and price evaluation, the DERP did not significantly delay new drug registration in Korea.

Conclusion
This study showed that the policies of the product patent system, GMP policies, and DERP regulations have significantly encouraged pharmaceutical companies to strive to meet regulatory requirements and promote innovation in Korea. The study suggests that it is necessary for companies to pre-emptively respond to systemic changes in development and production strategies to deal with regulatory changes and achieve sustainable growth. Also, our study results indicate that since government policies motivate the innovative system of the pharmaceutical industry, governmental authorities, when formulating pharmaceutical policies, need to consider the impact on the long-term innovation of the industry.