bluuebunny/crossref_metadata_2025_split huggingface dataset:
CYP4 subfamily V member 2 (CYP4V2) polymorphisms were associated with ischemic stroke in Chinese Han population
Authors: Long Faqing , Wang Desheng , Su Qingjie , Zhang Yuhui , Li Jianhong , Xia Shiliang , Wang Hailun , Wu Yongping , Qu Qiumin 
Published: November 2022

Abstract
Background
CYP4 subfamily V member 2 (CYP4V2) polymorphisms are related to venous thromboembolism. However, the influence of CYP4V2 polymorphisms on the susceptibility to ischemic stroke (IS) remains undetermined.

Methods
We selected and genotyped five polymorphisms of CYP4V2 in 575 cases and 575 controls to test whether CYP4V2 variants were associated with the risk for IS in a Chinese Han population. Genotyping of CYP4V2 polymorphisms was performed using the Agena MassARRAY platform. Logistic regression analysis was used to assess the association between CYP4V2 polymorphisms and IS risk by calculating odds ratios (ORs) and 95% confidence interval (CI). False-positive report probability analysis was applied to assess the noteworthy relationship of the significant findings.

Results
CYP4V2 rs1398007 might be a risk factor for IS (OR = 1.34, 95% CI 1.05–1.71, p = 0.009). Specially, confounding factors (age, gender, smoking and drinking status) might affect the relationship between rs1398007 and IS susceptibility. Moreover, rs1053094 and rs56413992 were associated with IS risk in males. Multifactor dimensionality reduction analysis showed the combination of rs13146272 and rs3736455 had the strongest interaction effect (information gain value of 0.40%). Furthermore, genotypes of rs1398007 (p = 0.006) and rs1053094 (p = 0.044) were associated with the levels of high-density lipoprotein cholesterol (HDL-C) among healthy controls.

Conclusion
Our results first provided evidence that CYP4V2 rs1398007 might be a risk factor for IS, which provides instructive clues for studying the mechanisms of CYP4V2 to the pathogenesis of IS.
Endotrophin is a risk marker of complications in CANagliflozin cardioVascular Assessment Study (CANVAS): a randomized controlled trial
Authors: Rasmussen Daniel Guldager Kring , Hansen Michael K. , Blair Joseph , Jatkoe Timothy A. , Neal Bruce , Karsdal Morten A. , Genovese Federica 
Published: November 2022

AbstractBackgroundEnhanced de-novo collagen type VI (COL VI) formation has been associated with kidney and cardiovascular fibrosis. We hypothesized that endotrophin (ETP), a product specifically generated during collagen type VI formation, may be prognostic for heart failure (HF), cardiovascular death (CVD), kidney endpoints, and all-cause mortality in patients with type 2 diabetes.MethodsWe measured ETP in plasma (P-ETP) and urine (U-ETP) samples collected at baseline and follow-up (year 3) from the randomized controlled trial, CANagliflozin cardioVascular Assessment Study (CANVAS), by use of the PRO-C6 ELISA measuring COL VI formation and ETP. At baseline, plasma and urine samples were available for 3531 and 3423 patients, respectively. At year 3, plasma and urine samples were available for 2178 (61.7%) and 2070 (60.5%) patients, respectively Patients were followed for a median of 6.1 years, and endpoints included: incident HF, CVD, three kidney composite endpoints, and all-cause mortality. Backward selection was used to identify variables to be included in the analyses. Robustness of the association with outcome was assessed by bootstrap analyses.ResultsIn univariable analysis, P-ETP predicted all investigated outcomes (all p < 0.0001), remained independently associated with all outcomes after adjustment for conventional risk factors (all p < 0.004), and increased C-statistics of the models for the outcomes HF, CVD, HFCVD, all-cause mortality, and kidney composite 2 (ΔC ≥ 0.002). In bootstrap analysis, P-ETP was retained with a frequency ranging from 41.0 to 98.4% for all outcomes. Levels of U-ETP were associated with outcomes in univariable analysis, but associations with most outcomes were lost after adjustment for conventional risk factors. The increase in P-ETP over time was greater with increasing albuminuria stage (p < 0.0001) and was independently associated with the kidney endpoints (p < 0.03). In the placebo arm, the increase in P-ETP was prognostic for all-cause mortality (HR [95% CI]; 1.14 [1.05–1.23], p = 0.003). Whereas levels of P-ETP were not impacted by treatment, levels of U-ETP significantly increased with canagliflozin treatment.ConclusionsP-ETP generated during COL VI formation predicts cardiovascular, kidney and mortality outcomes in patients with type 2 diabetes. As ETP identifies patients at increased risk of experiencing relevant outcomes, it may be used for patient enrichment in future clinical trials.Trial Registry Number(ClinicalTrials.gov Identifier): NCT01032629
Drug resistance of Plasmodium falciparum and Plasmodium vivax isolates in Indonesia
Authors: Rahmasari Farindira Vesti , Asih Puji B. S. , Dewayanti Farahana K. , Rotejanaprasert Chawarat , Charunwatthana Prakaykaew , Imwong Mallika , Syafruddin Din 
Published: November 2022

AbstractThis review article aims to investigate the genotypic profiles of Plasmodium falciparum and Plasmodium vivax isolates collected across a wide geographic region and their association with resistance to anti-malarial drugs used in Indonesia. A systematic review was conducted between 1991 and date. Search engines, such as PubMed, Science Direct, and Google Scholar, were used for articles published in English and Indonesian to search the literature. Of the 471 initially identified studies, 61 were selected for 4316 P. falciparum and 1950 P. vivax individual infections. The studies included 23 molecular studies and 38 therapeutic efficacy studies. K76T was the most common pfcrt mutation. K76N (2.1%) was associated with the haplotype CVMNN. By following dihydroartemisinin–piperaquine (DHA–PPQ) therapy, the mutant pfmdr1 alleles 86Y and 1034C were selected. Low prevalence of haplotype N86Y/Y184/D1246Ypfmdr1 reduces susceptibility to AS–AQ. SNP mutation pvmdr1 Y976F reached 96.1% in Papua and East Nusa Tenggara. Polymorphism analysis in the pfdhfr gene revealed 94/111 (84.7%) double mutants S108N/C59R or S108T/A16V in Central Java. The predominant pfdhfr haplotypes (based on alleles 16, 51, 59,108, 164) found in Indonesia were ANCNI, ANCSI, ANRNI, and ANRNL. Some isolates carried A437G (35.3%) or A437G/K540E SNPs (26.5%) in pfdhps. Two novel pfdhps mutant alleles, I588F/G and K540T, were associated with six pfdhps haplotypes. The highest prevalence of pvdhfr quadruple mutation (F57L/S58R/T61M/S117T) (61.8%) was detected in Papua. In pvdhps, the only polymorphism before and after 2008 was 383G mutation with 19% prevalence. There were no mutations in the pfk13 gene reported with validated and candidate or associated k13 mutation. An increased copy number of pfpm2, associated with piperaquine resistance, was found only in cases of reinfection. Meanwhile, mutation of pvk12 and pvpm4 I165V is unlikely associated with ART and PPQ drug resistance. DHA–PPQ is still effective in treating uncomplicated falciparum and vivax malaria. Serious consideration should be given to interrupt local malaria transmission and dynamic patterns of resistance to anti-malarial drugs to modify chemotherapeutic policy treatment strategies. The presence of several changes in pfk13 in the parasite population is of concern and highlights the importance of further evaluation of parasitic ART susceptibility in Indonesia.

Graphical Abstract
Life-threatening paradoxical thromboembolism in a patient with patent foramen ovale
Authors: Rizza Antonio , Negro Francesco , Gasbarri Tommaso , Arpesani Roberto , Ferro Baldassare , Roncucci Paolo , Palmieri Cataldo , Sorbo Simone , Pasanisi Emilio Maria , Solinas Marco , Berti Sergio 
Published: November 2022

Abstract
Background
Venous thromboembolism represents the third most frequent acute cardiovascular syndrome worldwide. Its clinical manifestations are deep vein thrombosis and/or pulmonary embolism. Despite a considerable mortality, diagnosis is often missed.

Case presentation
We report the management of a female patient with high-risk pulmonary thromboembolism treated initially with thromboaspiration, complicated by embolus jailing in a patent foramen ovale. In this situation, left cardiac chambers and systemic circulation were jeopardized by this floating embolus.

Conclusions
High-risk pulmonary embolism requires reperfusion strategy but sometimes mechanical thromboaspiration may be not fully successful; transesophageal echocardiography led to a prompt diagnosis of this unexpected finding; in this very particular case, open surgery represented a bail-out procedure to avoid cerebral and systemic embolism.
Healthcare costs associated with comorbid cardiovascular and renal conditions among persons with diabetes, 2008–2019
Authors: Shah Chintal H. , Dave Chintan V. 
Published: November 2022

Abstract
Background
There is paucity of data examining healthcare costs among persons with comorbid diabetes and cardiorenal conditions.

Objective
To elucidate the longitudinal trends and quantify the incremental healthcare costs associated with the following cardiorenal conditions: atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and kidney disease, among persons with diabetes.

Methods
Medical Expenditure Panel Survey data (2008–2019) were used to identify adults with diabetes and comorbid cardiorenal conditions. Overall, medical and pharmaceutical costs were ascertained (in 2019 US dollars). Analyses were adjusted for 14 variables using a two-part regression model.

Results
Among 32,519 adults with diabetes, the mean (standard error [SE]) annual healthcare costs were $13,829 ($213), with medical and prescription components contributing $9301 ($172) and $4528 ($98), respectively. Overall healthcare costs rose by 26.8% from $12,791 (2008–2009) to $16,215 (2018–2019) over the study period, driven by 42.5% and 20.3% increase in pharmaceutical and medical spending, respectively. Similar trends were observed for subgroup of persons with cardiorenal conditions. Compared to their counterparts without cardiorenal conditions and prior to adjustment, persons with ASCVD, HF and kidney disease incurred healthcare costs that were approximately 2.2, 3.3, and 2.7 times greater. After adjustment, comorbid ASCVD, HF and kidney disease were associated with annual excess spending of $8651 (95% CI $7729–$9573), $9373 (95% CI $9010–$9736), and $9995 (95% CI $8781–$11,209), respectively.

Conclusions
Study results are generalizable to non-institutionalized US persons. Healthcare costs associated with the management of diabetes are high—especially among those with comorbid cardiorenal conditions, and have risen in recent years.
Epigenetically regulated PCDHB15 impairs aggressiveness of metastatic melanoma cells
Authors: Carrier Arnaud , Desjobert Cécile , Lobjois Valérie , Rigal Lise , Busato Florence , Tost Jörg , Ensenyat-Mendez Miquel , Marzese Diego M. , Pradines Anne , Favre Gilles , Lamant Laurence , Lanfrancone Luisa , Etievant Chantal , Arimondo Paola B. , Riond Joëlle 
Published: November 2022

AbstractThe protocadherin proteins are cell adhesion molecules at the crossroad of signaling pathways playing a major role in neuronal development. It is now understood that their role as signaling hubs is not only important for the normal physiology of cells but also for the regulation of hallmarks of cancerogenesis. Importantly, protocadherins form a cluster of genes that are regulated by DNA methylation. We have identified for the first time that PCDHB15 gene is DNA-hypermethylated on its unique exon in the metastatic melanoma-derived cell lines and patients’ metastases compared to primary tumors. This DNA hypermethylation silences the gene, and treatment with the DNA demethylating agent 5-aza-2′-deoxycytidine reinduces its expression. We explored the role of PCDHB15 in melanoma aggressiveness and showed that overexpression impairs invasiveness and aggregation of metastatic melanoma cells in vitro and formation of lung metastasis in vivo. These findings highlight important modifications of the methylation of the PCDHβ genes in melanoma and support a functional role of PCDHB15 silencing in melanoma aggressiveness.
Gestational age acceleration is associated with epigenetic biomarkers of prenatal physiologic stress exposure
Authors: Euclydes Verônica , Gomes Catarina , Gouveia Gisele , Gastaldi Vinicius Daguano , Feltrin Arthur Sant’Anna , Camilo Caroline , Vieira Rossana Pulcineli , Felipe-Silva Aloísio , Grisi Sandra , Fink Günther , Brentani Alexandra , Brentani Helena 
Published: November 2022

Abstract
Background
Physiological maternal stress response, such as imbalance in the glucocorticoid pathway and immune system seems to be mediated by DNA methylation (DNAm) and might translate intrauterine stress exposures into phenotypic changes in a sex-specific manner. DNAm in specific sites can also predict newborn gestational age and gestational age acceleration (GAA). GAA occurs when the predicted biological age is higher than the chronological age. In adults, poor health outcomes related to this deviance are well documented and raise questions for the interpretation and prediction in early stages of life. Boys seem to be more vulnerable to intrauterine stress exposure than girls; however, the mechanisms of adaptive sex-specific responses are still unclear. We hypothesize that intrauterine stress exposure is associated with GAA and could be different in boys and girls if inflammatory or glucocorticoid pathways exposure is considered.

Results
Using the Western Region Birth Cohort (ROC—São Paulo, Brazil) (n = 83), we calculated DNAm age and GAA from cord blood samples. Two epigenetic risk scores were calculated as an indirect proxy for low-grade inflammation (i-ePGS) and for glucocorticoid exposure (GES). Multivariate linear regression models were applied to investigate associations of GAA with prenatal exposures. The i-ePGS and GES were included in different models with the same co-variates considering sex interactions. The first multivariate model investigating inflammatory exposure (adj. R2 = 0.31, p =  < 0.001) showed that GAA was positively associated with i-ePGS (CI, 0.26–113.87, p = 0.049) and negative pregnancy-related feelings (CI, 0.04–0.48 p = 0.019). No sex interaction was observed. The second model investigating glucocorticoid exposure (adj. R2 = 0.32, p =  < 0.001) showed that the higher was the GAA was associated with a lower the lower was the GES in girls (CI, 0.04–2.55, p = 0.044). In both models, maternal self-reported mental disorder was negatively associated with GAA.

Conclusion
Prenatal epigenetic score of exposure to low-grade inflammatory was a predictor of GAA for both sexes. Glucocorticoid epigenetic score seems to be more important to GAA in girls. This study supports the evidence of sex-specificity in stress response, suggesting the glucocorticoid as a possible pathway adopted by girls to accelerate the maturation in an adverse condition.
The economic valuation of Gedo Natural Forest conservation benefits, Ethiopia
Authors: Tolera Tadesse 
Published: November 2022

AbstractForest ecosystem economic valuation is responsible for ecologically aware and reasonable gains to the country and particularly to the surrounding groups through different means. Thus, the central objective of this study was to analyze the economic valuation Gedo Natural Forest conservation benefits of using the contingent valuation method. Both primary and secondary data were employed in this study. The interview responses of 342 households nominated from three kebeles around Gedo natural forest were collected in purpose and random sampling procedures through a semi-structure questionnaire. The mean willingness to pay calculated by means of Krinsky–Robb technique after running of Seemingly Unrelated Bivariate Probit Regression from the dichotomous choice format and open-ended questions was 24.97 and 23.91 birr per year, respectively. The outcomes of Tobit model show that the total livestock unit, total annual income of the household, and the amount of credit utilization are meaningful variables positively and significantly related to the likelihood of willingness to pay for the conservation benefits of Gedo natural forest. On the other hand, the households’ family size, the households’ age, and initial bid value were other important variables negatively and significantly influence households’ willingness to pay for the conservation benefits of Gedo natural forest. The liable body could, therefore, apply the scenario of willingness to pay in the study area, so that the Gedo natural forest could be conserved, measurable benefit to the households could be practical, and future awareness of respective household could be raised.
A pilot assessment of the career and job satisfaction of the pharmaceutical workforce in Lebanon
Authors: Nassar Elsa , Kassouf Sibelle , Hajj Aline , Sacre Hala , Akel Marwan , Zeenny Rony M. , Haddad Chadia , Salameh Pascale 
Published: November 2022

Abstract
Background
Lebanon has been recognized as a center for high-quality healthcare services in the Middle East because of its prestigious facilities certified by international bodies, competent health workers, and credible pharmaceutical sector. This study assessed the professional situation of the Lebanese pharmaceutical workforce upon graduation and entry to the job market. It also evaluated the satisfaction of pharmacists with the financial, physical, and psychological aspects of their job and the effect of the current socioeconomic crisis on their profession.

Methods
A cross-sectional study was performed between January and May 2021 among 114 Lebanese pharmacists from all pharmaceutical sectors across Lebanon. A self-administered questionnaire was elaborated to assess the pharmaceutical workforce in Lebanon. The online questionnaire was built using Google Forms and disseminated via emails and social platforms.

Results
Fresh graduates seemed more oriented toward community pharmacies, and 78.1% of the participants worked at least once in their lifetime in a community pharmacy. Pharmacists from the public university worked predominantly in the community pharmacy sector, while those who graduated from private universities worked mainly as medical representatives. Hospital pharmacy comprised significantly more PharmD graduates than other sectors; medical representatives had mainly a BS pharmacy, while those working as industrial pharmacists had a Master’s degree. A low percentage (31.6%) of participants found it easy to get hold of a job across different pharmaceutical sectors while 64.0% considered the internships experience insufficient to get employed. Nearly half (48.2%) of the respondents were poorly satisfied with their job, and 54.0% of community pharmacists reported not working in their preferred field compared to 39.1% of pharmacists from other sectors. Also, 65.79% felt that the economic crisis and the consequent medication shortages affected their credibility and how society perceived them. About half (45.61%) of the participants reported that their employment status was not affected by the crisis; the rest got a second job to cover their expenses (15.79%) or changed jobs (14.91%).

Conclusion
Our study findings revealed that most Lebanese fresh graduates worked as community pharmacists, which does not correspond to their preference, the available job market, and the modern pharmacy wingspan. Most pharmacists were also financially, physically, and emotionally dissatisfied due to the Lebanese economic crisis that added heavy workloads and responsibilities without any financial raise.
Normal variation of infant hip development
Authors: Hareendranathan Abhilash R. , Wichuk Stephanie , Punithakumar Kumaradevan , Dulai Sukhdeep , Jaremko Jacob 
Published: November 2022

Aims Studies of infant hip development to date have been limited by considering only the changes in appearance of a single ultrasound slice (Graf’s standard plane). We used 3D ultrasound (3DUS) to establish maturation curves of normal infant hip development, quantifying variation by age, sex, side, and anteroposterior location in the hip. Methods We analyzed 3DUS scans of 519 infants (mean age 64 days (6 to 111 days)) presenting at a tertiary children’s hospital for suspicion of developmental dysplasia of the hip (DDH). Hips that did not require ultrasound follow-up or treatment were classified as ‘typically developing’. We calculated traditional DDH indices like α angle (αSP), femoral head coverage (FHCSP), and several novel indices from 3DUS like the acetabular contact angle (ACA) and osculating circle radius (OCR) using custom software. Results α angle, FHC, and ACA indices increased and OCR decreased significantly by age in the first four months, mean αSP rose from 62.2° (SD 5.7°) to 67.3° (SD 5.2°) (p < 0.001) in one- to eight- and nine- to 16-week-old infants, respectively. Mean αSP and mean FHCSP were significantly, but only slightly, lower in females than in males. There was no statistically significant difference in DDH indices observed between left and right hip. All 3DUS indices varied significantly between anterior and posterior section of the hip. Mean 3D indices of α angle and FHC were significantly lower anteriorly than posteriorly: αAnt = 58.2° (SD 6.1°), αPost = 63.8° (SD 6.3°) (p < 0.001), FHCAnt = 43.0 (SD 7.4), and FHCPost = 55.4° (SD 11.2°) (p < 0.001). Acetabular rounding measured byOCR indices was significantly greater in the anterior section of the hip (p < 0.001). Conclusion We used 3DUS to show that hip shape and normal growth pattern vary significantly between anterior and posterior regions, by magnitudes similar to age-related changes. This highlights the need for careful selection of the Graf plane during 2D ultrasound examination. Whole-joint evaluation by obtaining either 3DUS or manual ‘sweep’ video images provides more comprehensive DDH assessment. Cite this article: Bone Jt Open 2022;3(11):913–923.