bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of interleukin 6 -174 G/C polymorphism with coronary artery disease and circulating IL-6 levels: a systematic review and meta-analysis
Authors: Rai Himanshu , Colleran Roisin , Cassese Salvatore , Joner Michael , Kastrati Adnan , Byrne Robert A. 
Published: September 2021

Abstract
Introduction
Circulating IL-6 levels and at least one polymorphic form of IL6 gene (IL6 -174 G/C, rs1800795) have been shown to be independently associated with coronary artery disease (CAD) by several investigators. Despite more than 12 published meta-analyses on this subject, association of -174 G/C with CAD, especially amongst distinct ancestral population groups remain unclear. We, therefore, conducted a systematic review and an updated meta-analysis to comprehensively ascertain the association of IL6 -174 G/C with CAD and circulating IL-6 levels.

Materials and methods
Relevant case–control/cohort studies investigating association of -174 G/C with CAD and circulating IL-6 levels were identified following a comprehensive online search. Association status for CAD was determined for the pooled sample, as well as separately for major ancestral subgroups. Association status for circulating IL-6 levels was assessed for the pooled sample, as well as separately for CAD cases and CAD free controls. Study-level odds ratios (OR) and 95% confidence intervals (CI) were pooled using random/fixed-effects model.

Results
Quantitative synthesis for the CAD endpoint was performed using 55 separate qualifying studies with a collective sample size of 51,213 (19,160 cases/32,053 controls). Pooled association of -174 G/C with CAD was found to be statistically significant through dominant (OR 1.15; 95% CI 1.05–1.25, p = 0.002) as well as allelic genetic model comparisons (OR 1.13, 95% CI 1.06–1.21, p = 0.0003). This effect was largely driven by Asian and Asian Indian ancestral subgroups, which also showed significant association with CAD in both genetic model comparisons (OR range 1.29–1.53, p value range ≤ 0.02). Other ancestral subgroups failed to show any meaningful association.
Circulating IL-6 levels were found to be significantly higher amongst the ‘C’ allele carriers in the pooled sample (Standard mean difference, SMD 0.11, 95% CI 0.01–0.22 pg/ml, p = 0.009) as well as in the CAD free control subgroup (SMD 0.10, 95% CI 0.02–0.17 pg/ml, p = 0.009), though not in the CAD case subgroup (SMD 0.17, 95% CI = − 0.02 to 0.37, p = 0.12).

Conclusions
The present systematic review and meta-analysis demonstrate an overall association between IL6 -174 G/C polymorphism and CAD, which seems to be mainly driven by Asian and Asian Indian ancestral subgroups. Upregulation of plasma IL-6 levels in the ‘C’ allele carriers seems to be at least partly responsible for this observed association. This warrants further investigations with large, structured case–control studies especially amongst Asian and Asian Indian ancestral groups.
Revidierte Diagnosekriterien für die Neurofibromatose Typ 1 (NF1) ermöglichen eine frühe präzise differenzialdiagnostische Abgrenzung zu anderen RASopathien und erleichtern die Diagnose
Authors: Kehrer-Sawatzki H. , Farschtschi S. , Mautner V.-F. 
Published: September 2021

Zusammenfassung
Hintergrund
Die Neurofibromatose Typ 1 (NF1) ist eines der häufigsten erblichen Tumorprädispositionssyndrome und zählt zu den RASopathien, einer Gruppe von Erkrankungen mit überlappender Symptomatik, die durch Störungen des RAS-vermittelten Signaltransduktionsweges entstehen. Die diagnostischen Kriterien für NF1 sind 1988 definiert worden. Neue klinische und genetische Erkenntnisse erforderten eine Revision dieser Kriterien. Besonders im frühen Kindesalter ermöglichen die NF1-Diagnosekriterien von 1988 häufig noch keine Diagnose der NF1 und keine differenzialdiagnostische Abgrenzung zu anderen RASopathien wie dem Legius-Syndrom.

Methoden
Es erfolgte eine selektive Literaturrecherche zu Genetik und Symptomatik der NF1. Die Autoren nahmen an einer Delphi-Methode zur Revision der NF1-Diagnosekriterien durch ein internationales Expertengremium teil. Es wurden hierbei auch erstmalig die Diagnosekriterien für das Legius-Syndrom sowie für Mosaikformen beider Erkrankungen erstellt.

Ergebnisse
Die NF1-Diagnosekriterien wurden überarbeitet; dabei wurden neue klinische Merkmale wie choroidale Anomalien aufgenommen, aber auch genetische Befunde wie der Nachweis pathogener NF1-Genvarianten.

Diskussion
Mit den revidierten NF1-Diagnosekriterien und den neu erstellten Diagnosekriterien für das Legius-Syndrom ist es nun möglich, auch bei Kindern die Diagnose einer NF1 mit hoher Sensitivität und Spezifität frühzeitig zu stellen. Diese Diagnosekriterien ermöglichen eine genaue differenzialdiagnostische Abgrenzung von anderen Erkrankungen mit phänotypischen Überlappungen zur NF1, was eine frühe Risikostratifizierung und somit eine zielgerichtete Behandlung und Betreuung der Patienten ermöglicht.
The importance of increasing population diversity in genetic studies of type 2 diabetes and related glycaemic traits
Authors: Barroso Inês 
Published: September 2021

AbstractType 2 diabetes has a global prevalence, with epidemiological data suggesting that some populations have a higher risk of developing this disease. However, to date, most genetic studies of type 2 diabetes and related glycaemic traits have been performed in individuals of European ancestry. The same is true for most other complex diseases, largely due to use of ‘convenience samples’. Rapid genotyping of large population cohorts and case–control studies from existing collections was performed when the genome-wide association study (GWAS) ‘revolution’ began, back in 2005. Although global representation has increased in the intervening 15 years, further expansion and inclusion of diverse populations in genetic and genomic studies is still needed. In this review, I discuss the progress made in incorporating multi-ancestry participants in genetic analyses of type 2 diabetes and related glycaemic traits, and associated opportunities and challenges. I also discuss how increased representation of global diversity in genetic and genomic studies is required to fulfil the promise of precision medicine for all.
Graphical abstract
Effectiveness of a polyphenolic extract (Lippia citriodora and Hibiscus sabdariffa) on appetite regulation in overweight and obese grade I population: an 8-week randomized, double-blind, cross-over, placebo-controlled trial
Authors: Serna Ana , Marhuenda Javier , Arcusa Raúl , Pérez-Piñero Silvia , Sánchez-Macarro Maravillas , García-Muñoz Ana María , Victoria-Montesinos Desirée , Cánovas Fernando , López-Román F. Javier 
Published: September 2021

AbstractIntroductionPolyphenols have shown capacity to improve appetite sensation, leading to enhanced control of body weight. However, despite being related with hunger-related hormones, metabolic and mechanism are not well known.MethodsThe effectiveness of a nutraceutical composed of extract toLippia citriodoraandHibiscus sabdarrifa(Lc-Hs) for controlling satiety and hunger was analyzed in a cross-over, placebo-controlled (Pla) clinical intervention. The study was divided in two 60-day periods separated by 30-day length wash-out period. At the end of each period, overweight and obese subjects (n = 33; age = 33.76 ± 12.23; BMI = 28.20 kg/m2 ± 2.47; fat mass 30.65 ± 8.39%; both sexes were proposed to eat an ad-libitum meal. Meanwhile, appetite sensation was determined by visual analog scales at different times. Moreover, blood extraction was performed to determine biochemical parameters (lipid and glucidic profile and safety parameters) and to evaluate hunger-related hormones (insulin, leptin, ghrelin, adiponectin, GLP-1 and peptide YY).ResultsA decrease in appetite sensation was observed in Lc-Hs treatment, showing higher satiety quotient (Pla = 3.36 ± 2.33%mm/kcal; Lc-Hs = 5.53 ± 2.91%mm/kcal;p < 0.0001). Area under the curve was higher in Pla compared to Lc-Hs during the test, from baseline to minute 240 (240 (Pla 9136.65 ± 2261.46%xmin−1; Lc-Hs 8279.73 ± 2745.71%xmin−1;p < 0.014). Energy consumption was lower for subjects treated with Lc-Hs (774.44 ± 247.77 kcal) compared to those treated with Pla (849.52 ± 246.54 kcal) (p < 0.004). Leptin values varied from baseline (Pla 12.36 ± 1.98 ng/mL; Lc-Hs 13.13 ± 1.99 ng/mL) to the end of the study (Pla 12.60 ± 2.02 ng/mL; Lc-Hs 12.06 ± 2.05 ng/mL;p < 0.047). GLP-1 values varied (p < 0.001) in Lc-Hs treatment from baseline (4.34 ± 0.49 ng/mL) to the end of the study (3.23 ± 0.52 ng/mL).ConclusionThe supplementation with the Lc-Hs extract decreases appetite sensation in overweight and obese population, reducing calorie intake after an ad-libitum meal. Due to variation on hunger-related hormones and the relationship between satiety feeling, it would be interesting to develop future research focused on the variation of the hormones themselves.
Joint optic disc and cup segmentation based on multi-scale feature analysis and attention pyramid architecture for glaucoma screening
Authors: Sun Guangmin , Zhang Zhongxiang , Zhang Junjie , Zhu Meilong , Zhu Xiao-rong , Yang Jin-Kui , Li Yu 
Published: September 2021

AbstractAutomatic segmentation of optic disc (OD) and optic cup (OC) is an essential task for analysing colour fundus images. In clinical practice, accurate OD and OC segmentation assist ophthalmologists in diagnosing glaucoma. In this paper, we propose a unified convolutional neural network, named ResFPN-Net, which learns the boundary feature and the inner relation between OD and OC for automatic segmentation. The proposed ResFPN-Net is mainly composed of multi-scale feature extractor, multi-scale segmentation transition and attention pyramid architecture. The multi-scale feature extractor achieved the feature encoding of fundus images and captured the boundary representations. The multi-scale segmentation transition is employed to retain the features of different scales. Moreover, an attention pyramid architecture is proposed to learn rich representations and the mutual connection in the OD and OC. To verify the effectiveness of the proposed method, we conducted extensive experiments on two public datasets. On the Drishti-GS database, we achieved a Dice coefficient of 97.59%, 89.87%, the accuracy of 99.21%, 98.77%, and the Averaged Hausdorff distance of 0.099, 0.882 on the OD and OC segmentation, respectively. We achieved a Dice coefficient of 96.41%, 83.91%, the accuracy of 99.30%, 99.24%, and the Averaged Hausdorff distance of 0.166, 1.210 on the RIM-ONE database for OD and OC segmentation, respectively. Comprehensive results show that the proposed method outperforms other competitive OD and OC segmentation methods and appears more adaptable in cross-dataset scenarios. The introduced multi-scale loss function achieved significantly lower training loss and higher accuracy compared with other loss functions. Furthermore, the proposed method is further validated in OC to OD ratio calculation task and achieved the best MAE of 0.0499 and 0.0630 on the Drishti-GS and RIM-ONE datasets, respectively. Finally, we evaluated the effectiveness of the glaucoma screening on Drishti-GS and RIM-ONE datasets, achieving the AUC of 0.8947 and 0.7964. These results proved that the proposed ResFPN-Net is effective in analysing fundus images for glaucoma screening and can be applied in other relative biomedical image segmentation applications.
Second-line pembrolizumab versus chemotherapy in Japanese patients with advanced esophageal cancer: subgroup analysis from KEYNOTE-181
Authors: Muro Kei , Kojima Takashi , Moriwaki Toshikazu , Kato Ken , Nagashima Fumio , Kawakami Hisato , Ishihara Ryu , Ogata Takashi , Satoh Taroh , Iwakami Keiichi , Han Shirong , Yatsuzuka Naoyoshi , Takami Tomoko , Bhagia Pooja , Doi Toshihiko 
Published: September 2021

Abstract
Background
Safe and effective treatments for advanced esophageal cancer are an unmet need in Japan. We report results of a subgroup analysis of Japanese patients enrolled in KEYNOTE-181, a randomized, open-label, phase 3 study of pembrolizumab versus chemotherapy as second-line therapy for patients with advanced or metastatic esophageal cancer whose disease progressed after standard first-line therapy.

Methods
Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg every 3 weeks or investigator’s choice of paclitaxel, docetaxel, or irinotecan. Efficacy was evaluated in all Japanese patients and in those with programmed death ligand 1 combined positive score ≥ 10.

Results
Of the 152 Japanese patients enrolled (pembrolizumab, n = 77; chemotherapy, n = 75), 150 (98.7%) had squamous cell carcinoma and 79 (52.0%) had combined positive score ≥ 10. At the final analysis, median overall survival was improved among all patients (12.4 vs 8.2 months with pembrolizumab and chemotherapy, respectively; hazard ratio, 0.68; 95% CI 0.48–0.97) and patients with combined positive score ≥ 10 (12.6 vs 8.4 months; hazard ratio, 0.68; 95% CI 0.42–1.10). Fewer patients had any-grade (74.0% vs 95.9%) or grade 3–5 (16.9 vs 50.0%) treatment-related adverse events with pembrolizumab than with chemotherapy.

Conclusion
Consistent with the global trial results, second-line pembrolizumab therapy showed a survival benefit and a favorable safety profile compared with chemotherapy in Japanese patients with advanced esophageal cancer.
Sacred natural sites and biodiversity conservation: a systematic review
Authors: Zannini Piero , Frascaroli Fabrizio , Nascimbene Juri , Persico Angela , Halley John Maxwell , Stara Kalliopi , Midolo Gabriele , Chiarucci Alessandro 
Published: September 2021

AbstractSacred natural sites (SNS) have gained recognition from conservationists, and are regarded as the oldest form of habitat protection in human history. Many case studies and literature reviews have been published on the subject. However, an updated and global-level synthesis on the effect of SNS on biodiversity conservation is still lacking. Here, we provide the first systematic review on SNS and biodiversity conservation, aiming to evaluate the effect of SNS across different: (i) continents; (ii) taxa; (iii) metrics. We checked 2750 papers and by applying inclusion criteria we selected 27 relevant papers. From these, we extracted descriptive data and 131 comparisons between SNS and Reference Sites. We applied vote-counting, multinomial and binomial post-hoc tests to the 131 comparisons. We found strong evidence that SNS have a positive effect on biodiversity, but also strong geographical and taxonomical biases, with most research focusing on Asia and Africa and on plants. We found that SNS have mainly positive effects on taxonomical diversity, vegetation structure and cultural uses of biodiversity. Our results strongly support the view that SNS have positive effects on biodiversity across continents and geographical settings, as found in a number of local studies and earlier overviews. These effects should be given official recognition in appropriate conservation frameworks, together with the specific forms of governance and management that characterize SNS. At the same time, further efforts are also required to fill the geographical and taxonomical gaps here highlighted, and to advancing our knowledge of SNS through more systematic research.
Role of non-coding RNAs in tumor progression and metastasis in pancreatic cancer
Authors: Sempere Lorenzo F. , Powell Katherine , Rana Jatin , Brock Andrew A. , Schmittgen Thomas D. 
Published: September 2021

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with an overall 5-year survival rate of less than 10%. The 1-year survival rate of patients with locally advanced or metastatic disease is abysmal. The aggressive nature of cancer cells, hypovascularization, extensive desmoplastic stroma, and immunosuppressive tumor microenvironment (TME) endows PDAC tumors with multiple mechanisms of drug resistance. With no obvious genetic mutation(s) driving tumor progression or metastatic transition, the challenges for understanding the biological mechanism(s) of these processes are paramount. A better understanding of the molecular and cellular mechanisms of these processes could lead to new diagnostic tools for patient management and new targets for therapeutic intervention. microRNAs (miRNAs) are an evolutionarily conserved gene class of short non-coding regulatory RNAs. miRNAs are an extensive regulatory layer that controls gene expression at the posttranscriptional level. This review focuses on preclinical models that functionally dissect miRNA activity in tumor progression or metastatic processes in PDAC. Collectively, these studies suggest an influence of miRNAs and RNA-RNA networks in the processes of epithelial to mesenchymal cell transition and cancer cell stemness. At a cell-type level, some miRNAs mainly influence cancer cell–intrinsic processes and pathways, whereas other miRNAs predominantly act in distinct cellular compartments of the TME to regulate fibroblast and immune cell functions and/or influence other cell types’ function via cell-to-cell communications by transfer of extracellular vesicles. At a molecular level, the influence of miRNA-mediated regulation often converges in core signaling pathways, including TGF-β, JAK/STAT, PI3K/AKT, and NF-κB.
Applying test case prioritization to software microbenchmarks
Authors: Laaber Christoph , Gall Harald C. , Leitner Philipp 
Published: September 2021

AbstractRegression testing comprises techniques which are applied during software evolution to uncover faults effectively and efficiently. While regression testing is widely studied for functional tests, performance regression testing, e.g., with software microbenchmarks, is hardly investigated. Applying test case prioritization (TCP), a regression testing technique, to software microbenchmarks may help capturing large performance regressions sooner upon new versions. This may especially be beneficial for microbenchmark suites, because they take considerably longer to execute than unit test suites. However, it is unclear whether traditional unit testing TCP techniques work equally well for software microbenchmarks. In this paper, we empirically study coverage-based TCP techniques, employing total and additional greedy strategies, applied to software microbenchmarks along multiple parameterization dimensions, leading to 54 unique technique instantiations. We find that TCP techniques have a mean APFD-P (average percentage of fault-detection on performance) effectiveness between 0.54 and 0.71 and are able to capture the three largest performance changes after executing 29% to 66% of the whole microbenchmark suite. Our efficiency analysis reveals that the runtime overhead of TCP varies considerably depending on the exact parameterization. The most effective technique has an overhead of 11% of the total microbenchmark suite execution time, making TCP a viable option for performance regression testing. The results demonstrate that the total strategy is superior to the additional strategy. Finally, dynamic-coverage techniques should be favored over static-coverage techniques due to their acceptable analysis overhead; however, in settings where the time for prioritzation is limited, static-coverage techniques provide an attractive alternative.
Graph representations in genetic programming
Authors: Françoso Dal Piccol Sotto Léo , Kaufmann Paul , Atkinson Timothy , Kalkreuth Roman , Porto Basgalupp Márcio 
Published: September 2021

AbstractGraph representations promise several desirable properties for genetic programming (GP); multiple-output programs, natural representations of code reuse and, in many cases, an innate mechanism for neutral drift. Each graph GP technique provides a program representation, genetic operators and overarching evolutionary algorithm. This makes it difficult to identify the individual causes of empirical differences, both between these methods and in comparison to traditional GP. In this work, we empirically study the behaviour of Cartesian genetic programming (CGP), linear genetic programming (LGP), evolving graphs by graph programming and traditional GP. By fixing some aspects of the configurations, we study the performance of each graph GP method and GP in combination with three different EAs: generational, steady-state and $$(1+\lambda )$$

(
1
+
λ
)

. In general, we find that the best choice of representation, genetic operator and evolutionary algorithm depends on the problem domain. Further, we find that graph GP methods can increase search performance on complex real-world regression problems and, particularly in combination with the ($$1 + \lambda$$

1
+
λ

) EA, are significantly better on digital circuit synthesis tasks. We further show that the reuse of intermediate results by tuning LGP’s number of registers and CGP’s levels back parameter is of utmost importance and contributes significantly to better convergence of an optimization algorithm when solving complex problems that benefit from code reuse.
Influence of lactide vs glycolide composition of poly (lactic-co-glycolic acid) polymers on encapsulation of hydrophobic molecules: molecular dynamics and formulation studies
Authors: Dobhal Anurag , Srivastav Ashu , Dandekar Prajakta , Jain Ratnesh 
Published: September 2021

AbstractThe work demonstrates the preparation of PLGA (PLGA 50:50, PLGA 75:25) nanoparticles, to encapsulate a hydrophobic molecule (coumarin-6), using the microreactor-based continuous process. The formulations were characterized using dynamic light scattering and transmission electron microscopy to determine their size, homogeneity, zeta potential, and surface morphology. The resulting nanoparticles were safe to the CHO cells (≈80% cell survival), at the concentration of ≤600 µg/mL and were successfully taken up by the cells, as demonstrated using confocal microscopy. Moreover, imaging flow cytometry confirmed that the nanoparticles were internalized in 73.96% of the cells. Furthermore, molecular dynamics simulation and docking studies were carried out to explore the effect of polymer chain length of PLGA and lactide vs glycolide (LA:GA) ratio on their compatibility with the coumarin-6 molecules and to study the coiling and flexibility of PLGA in the presence of coumarin-6 molecules. Flory–Huggins interaction parameter (χ) was calculated for polymer chains of varying lengths and LA:GA ratio, with respect to coumarin-6. χ parameter increased with increase in polymer chain length, which indicated superior interaction of coumarin-6 with the smaller chains. Amongst all the polymeric systems, PLGA55 exhibited the strongest interaction with coumarin-6, for all the chain lengths, possibly because of their homogeneous spatial arrangements and superior binding energy. PLGA27 showed better compatibility compared to PLGA72 and PGA, whereas PLA-based polymers exhibited the least compatibility. Analysis of the radius of gyration of the polymer chains in the polymer–coumarin-6 complexes, at the end of molecular dynamics run, exhibited that the polymer chains displayed varying coiling behavior and flexibility, depending upon the relative concentrations of the polymer and coumarin-6. Factors like intra-chain interactions, spatial arrangement, inter-chain binding energies, and polymer–coumarin-6 compatibility also influenced the coiling and flexibility of polymer chains.