bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of the COVID-19 Pandemic on the Social Inequalities of Health Care Use in Hungary: A Nationally Representative Cross-Sectional Study
Authors: Bekele Bayu Begashaw , Alhaffar Bahaa Aldin , Wasnik Rahul Naresh , Sándor János
Published: February 2022

Background: The social representation of restricted health care use during the COVID-19 pandemic has not been evaluated properly yet in Hungary. Objective: Our study aimed to quantify the effect of COVID-19 pandemic measures on general practitioner (GP) visits, specialist care, hospitalization, and cost-related prescription nonredemption (CRPNR) among adults, and to identify the social strata susceptible to the pandemic effect. Methods: This cross-sectional study was based on nationally representative data of 6611 (Nprepandemic = 5603 and Npandemic = 1008) adults. Multivariable logistic regression models were applied to determine the sociodemographic and clinical factors influencing health care use by odds ratios (ORs) along with the corresponding 95% confidence intervals (CI). To identify the social strata susceptible to the pandemic effect, the interaction of the time of data collection with the level of education, marital status, and Roma ethnicity, was tested and described by iORs. Results: While the CRPNR did not change, the frequency of GP visits, specialist care, and hospitalization rates was remarkably reduced by 22.2%, 26.4%, and 6.7%, respectively, during the pandemic. Roma proved to be not specifically affected by the pandemic in any studied aspect, and the pandemic restructuring of health care impacted the social subgroups evenly with respect to hospital care. However, the pandemic effect was weaker among primary educated adults (iORGP visits, high-school vs. primary-education = 0.434; 95% CI 0.243–0.776, ORspecialist visit, high-school vs. primary-education = 0.598; 95% CI 0.364–0.985), and stronger among married adults (iORGP visit, widowed vs. married = 2.284; 95% CI 1.043–4.998, iORspecialist visit, widowed vs. married = 1.915; 95% CI 1.157–3.168), on the frequency of GP visits and specialist visits. The prepandemic CRPNR inequality by the level of education was increased (iORhigh-school vs. primary-education = 0.236; 95% CI 0.075–0.743). Conclusion: Primary educated and widowed adults did not follow the general trend, and their prepandemic health care use was not reduced during the pandemic. This shows that although the management of pandemic health care use restrictions was implemented by not increasing social inequity, the drug availability for primary educated individuals could require more support.
Data Analytics Process over Road Accidents Data—A Case Study of Lisbon City
Authors: Mesquitela Joao , Elvas Luis B. , Ferreira Joao C , Nunes Luis
Published: February 2022

Traffic accidents in urban areas lead to reduced quality of life and added pressure in the cities’ infra-structures. In the context of smart city data is becoming available that allows a deeper analysis of the phenomenon. We propose a data fusion process from different information sources like road accidents, weather conditions, local authority reports tools, traffic, fire brigade. These big data analytics allow the creation of knowledge for local municipalities using local data. Data visualizations allow big picture overview. This paper presents an approach to the geo-referenced accident-hotspots identification. Using ArcGIS Pro, we apply Kernel Density and Hot Spot Analysis (Getis-Ord Gi*) tools, identifying the existence of black spots in terms of location and context conditions, and evaluate the possible human, environmental and circumstantial factors that may influence the severity of accidents. The results were validated by an expert committee. This approach can be applied to other cites wherever this data is available.
Design and Characterization of Myristoylated and Non-Myristoylated Peptides Effective against Candida spp. Clinical Isolates
Authors: Bugli Francesca , Massaro Federica , Buonocore Francesco , Saraceni Paolo Roberto , Borocci Stefano , Ceccacci Francesca , Bombelli Cecilia , Di Vito Maura , Marchitiello Rosalba , Mariotti Melinda , Torelli Riccardo , Sanguinetti Maurizio , Porcelli Fernando
Published: February 2022

The increasing resistance of fungi to antibiotics is a severe challenge in public health, and newly effective drugs are required. Promising potential medications are lipopeptides, linear antimicrobial peptides (AMPs) conjugated to a lipid tail, usually at the N-terminus. In this paper, we investigated the in vitro and in vivo antifungal activity of three short myristoylated and non-myristoylated peptides derived from a mutant of the AMP Chionodracine. We determined their interaction with anionic and zwitterionic membrane-mimicking vesicles and their structure during this interaction. We then investigated their cytotoxic and hemolytic activity against mammalian cells. Lipidated peptides showed a broad spectrum of activity against a relevant panel of pathogen fungi belonging to Candida spp., including the multidrug-resistant C. auris. The antifungal activity was also observed vs. biofilms of C. albicans, C. tropicalis, and C. auris. Finally, a pilot efficacy study was conducted on the in vivo model consisting of Galleria mellonella larvae. Treatment with the most-promising myristoylated peptide was effective in counteracting the infection from C. auris and C. albicans and the death of the larvae. Therefore, this myristoylated peptide is a potential candidate to develop antifungal agents against human fungal pathogens.
MicroRNAs and ‘Sponging’ Competitive Endogenous RNAs Dysregulated in Colorectal Cancer: Potential as Noninvasive Biomarkers and Therapeutic Targets
Authors: Jorgensen Brian G. , Ro Seungil
Published: February 2022

The gastrointestinal (GI) tract in mammals is comprised of dozens of cell types with varied functions, structures, and histological locations that respond in a myriad of ways to epigenetic and genetic factors, environmental cues, diet, and microbiota. The homeostatic functioning of these cells contained within this complex organ system has been shown to be highly regulated by the effect of microRNAs (miRNA). Multiple efforts have uncovered that these miRNAs are often tightly influential in either the suppression or overexpression of inflammatory, apoptotic, and differentiation-related genes and proteins in a variety of cell types in colorectal cancer (CRC). The early detection of CRC and other GI cancers can be difficult, attributable to the invasive nature of prophylactic colonoscopies. Additionally, the levels of miRNAs associated with CRC in biofluids can be contradictory and, therefore, must be considered in the context of other inhibiting competitive endogenous RNAs (ceRNA) such as lncRNAs and circRNAs. There is now a high demand for disease treatments and noninvasive screenings such as testing for bloodborne or fecal miRNAs and their inhibitors/targets. The breadth of this review encompasses current literature on well-established CRC-related miRNAs and the possibilities for their use as biomarkers in the diagnoses of this potentially fatal GI cancer.
Utilizing Genomically Targeted Molecular Data to Improve Patient-Specific Outcomes in Autism Spectrum Disorder
Authors: Hausman-Cohen Sharon , LaValley William , Way Heather , Gutierrez Emily , Reeder Jordan
Published: February 2022

Molecular biology combined with genomics can be a powerful tool for developing potential intervention strategies for improving outcomes in children with autism spectrum disorders (ASD). Monogenic etiologies rarely cause autism. Instead, ASD is more frequently due to many polygenic contributing factors interacting with each other, combined with the epigenetic effects of diet, lifestyle, and environment. One limitation of genomics has been identifying ways of responding to each identified gene variant to translate the information to something clinically useful. This paper will illustrate how understanding the function of a gene and the effects of a reported variant on a molecular level can be used to develop actionable and targeted potential interventions for a gene variant or combinations of variants. For illustrative purposes, this communication highlights a specific genomic variant, SHANK3. The steps involved in developing molecularly genomically targeted actionable interventions will be demonstrated. Cases will be shared to support the efficacy of this strategy and to show how clinicians utilized these targeted interventions to improve ASD-related symptoms significantly. The presented approach demonstrates the utility of genomics as a part of clinical decision-making.
Fatty Acid Metabolism in Ovarian Cancer: Therapeutic Implications
Authors: Yoon Hyunho , Lee Sanghoon
Published: February 2022

Ovarian cancer is the most malignant gynecological tumor. Previous studies have reported that metabolic alterations resulting from deregulated lipid metabolism promote ovarian cancer aggressiveness. Lipid metabolism involves the oxidation of fatty acids, which leads to energy generation or new lipid metabolite synthesis. The upregulation of fatty acid synthesis and related signaling promote tumor cell proliferation and migration, and, consequently, lead to poor prognosis. Fatty acid-mediated lipid metabolism in the tumor microenvironment (TME) modulates tumor cell immunity by regulating immune cells, including T cells, B cells, macrophages, and natural killer cells, which play essential roles in ovarian cancer cell survival. Here, the types and sources of fatty acids and their interactions with the TME of ovarian cancer have been reviewed. Additionally, this review focuses on the role of fatty acid metabolism in tumor immunity and suggests that fatty acid and related lipid metabolic pathways are potential therapeutic targets for ovarian cancer.
Allosteric Determinants of the SARS-CoV-2 Spike Protein Binding with Nanobodies: Examining Mechanisms of Mutational Escape and Sensitivity of the Omicron Variant
Authors: Verkhivker Gennady
Published: February 2022

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric determinants of the SARS-CoV-2 spike protein binding with nanobodies, we also examined nanobody-induced modulation of escaping mutations and the effect of the Omicron variant on nanobody binding. The mutational scanning analysis supported the notion that E484A mutation can have a significant detrimental effect on nanobody binding and result in Omicron-induced escape from nanobody neutralization. Our findings showed that SARS-CoV-2 spike protein might exploit the plasticity of specific allosteric hotspots to generate escape mutants that alter response to binding without compromising activity. The network analysis supported these findings showing that VHH E/VHH V nanobody binding can induce long-range couplings between the cryptic binding epitope and ACE2-binding site through a broader ensemble of communication paths that is less dependent on specific mediating centers and therefore may be less sensitive to mutational perturbations of functional residues. The results suggest that binding affinity and long-range communications of the SARS-CoV-2 complexes with nanobodies can be determined by structurally stable regulatory centers and conformationally adaptable hotspots that are allosterically coupled and collectively control resilience to mutational escape.
Genome-Wide Association Analysis and Genomic Prediction of Thyroglobulin Plasma Levels
Authors: Pleić Nikolina , Babić Leko Mirjana , Gunjača Ivana , Boutin Thibaud , Torlak Vesela , Matana Antonela , Punda Ante , Polašek Ozren , Hayward Caroline , Zemunik Tatijana
Published: February 2022

Thyroglobulin (Tg) is an iodoglycoprotein produced by thyroid follicular cells which acts as an essential substrate for thyroid hormone synthesis. To date, only one genome-wide association study (GWAS) of plasma Tg levels has been performed by our research group. Utilizing recent advancements in computation and modeling, we apply a Bayesian approach to the probabilistic inference of the genetic architecture of Tg. We fitted a Bayesian sparse linear mixed model (BSLMM) and a frequentist linear mixed model (LMM) of 7,289,083 variants in 1096 healthy European-ancestry participants of the Croatian Biobank. Meta-analysis with two independent cohorts (total n = 2109) identified 83 genome-wide significant single nucleotide polymorphisms (SNPs) within the ST6GAL1 gene (p<5×10−8). BSLMM revealed additional association signals on chromosomes 1, 8, 10, and 14. For ST6GAL1 and the newly uncovered genes, we provide physiological and pathophysiological explanations of how their expression could be associated with variations in plasma Tg levels. We found that the SNP-heritability of Tg is 17% and that 52% of this variation is due to a small number of 16 variants that have a major effect on Tg levels. Our results suggest that the genetic architecture of plasma Tg is not polygenic, but influenced by a few genes with major effects.
Interplay between Ca2+/Calmodulin-Mediated Signaling and AtSR1/CAMTA3 during Increased Temperature Resulting in Compromised Immune Response in Plants
Authors: Yuan Peiguo , Poovaiah B. W.
Published: February 2022

Changing temperatures are known to affect plant–microbe interactions; however, the molecular mechanism involved in plant disease resistance is not well understood. Here, we report the effects of a moderate change in temperature on plant immune response through Ca2+/calmodulin-mediated signaling. At 30 °C, Pst DC3000 triggered significantly weak and relatively slow Ca2+ influx in plant cells, as compared to that at 18 °C. Increased temperature contributed to an enhanced disease susceptibility in plants; the enhanced disease susceptibility is the result of the compromised stomatal closure induced by pathogens at high temperature. A Ca2+ receptor, AtSR1, contributes to the decreased plant immunity at high temperatures and the calmodulin-binding domain (CaMBD) is required for its function. Furthermore, both salicylic acid biosynthesis (ICS) and salicylic acid receptor (NPR1) are involved in this process. In addition to stomatal control, AtSR1 is involved in high temperature-compromised apoplastic immune response through the salicylic acid signaling pathway. The qRT-PCR data revealed that AtSR1 contributed to increased temperatures-mediated susceptible immune response by regulating SA-related genes in atsr1, such as PR1, ICS1, NPR1, as well as EDS1. Our results indicate that Ca2+ signaling has broad effects on the molecular interplay between changing temperatures as well as plant defense during plant–pathogen interactions.
Flavonoids—Natural Gifts to Promote Health and Longevity
Authors: Fan Xiaolan , Fan Ziqiang , Yang Ziyue , Huang Tiantian , Tong Yingdong , Yang Deying , Mao Xueping , Yang Mingyao
Published: February 2022

The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids.
Effects of Nitrogen Fertilizer on Quality Characteristics of Wheat with the Absence of Different Individual High-Molecular-Weight Glutenin Subunits (HMW-GSs)
Authors: Yang Tao , Zhou Qin , Wang Qi , Wang Xiao , Cai Jian , Huang Mei , Jiang Dong
Published: February 2022

High-molecular-weight glutenin subunits (HMW-GSs) are important components of gluten, which determine the grain quality of wheat. In this study, we investigated the effects of nitrogen (N) fertilizer application on the synthesis and accumulation of grain protein and gluten quality in wheat lines with different HMW-GSs absent. The results showed that the absence of the HMW-GS in the wheat variety Ningmai 9 significantly decreased the contents of gluten, glutenin macropolymer (GMP), protein compositions, HMW-GS and HMW-GS/LMW-GS. The reduction in glutenins was compensated to some extent by an increase of gliadins. The absence of x-type HMW-GSs (1, 7 and 2 subunits) had a greater effect on gluten and GMP properties than y-type HMW-GSs (8 and 12 subunits). The content of protein compositions, gluten and GMP increased with an increase of N level; however, the increment in wheat lines with the absence of HMW-GS, especially in Ax1a, Bx7a and Dx2a, was lower than that in the wild type under various N levels. The expression level of genes encoding HMW-GSs, and activities of nitrate reductase (NR) and glutamine synthetase (GS), differed significantly among the investigated wheat lines. The reduction in gene expression and activities in Ax1a and Dx2a may account for the reductions in gluten, GMP, protein compositions, HMW-GS and HMW-GS/LMW-GS.
CD44 Expression Intensity Marks Colorectal Cancer Cell Subpopulations with Different Extracellular Vesicle Release Capacity
Authors: Kelemen Andrea , Carmi Idan , Seress Iván , Lőrincz Péter , Tölgyes Tamás , Dede Kristóf , Bursics Attila , Buzás Edit I. , Wiener Zoltán
Published: February 2022

Extracellular vesicles (EV) are released by virtually all cells and they transport biologically important molecules from the release site to target cells. Colorectal cancer (CRC) is a leading cause of cancer-related death cases, thus, it represents a major health issue. Although the EV cargo may reflect the molecular composition of the releasing cells and thus, EVs may hold a great promise for tumor diagnostics, the impact of intratumoral heterogeneity on the intensity of EV release is still largely unknown. By using CRC patient-derived organoids that maintain the cellular and molecular heterogeneity of the original epithelial tumor tissue, we proved that CD44high cells produce more organoids with a higher proliferation intensity, as compared to CD44low cells. Interestingly, we detected an increased EV release by CD44high CRC cells. In addition, we found that the miRNA cargos of CD44high and CD44low cell derived EVs largely overlapped and only four miRNAs were specific for one of the above subpopulations. We observed that EVs released by CD44high cells induced the proliferation and activation of colon fibroblasts more strongly than CD44low cells. However, this effect was due to the higher EV number rather than to the miRNA cargo of EVs. Collectively, we identified CRC subpopulations with different EV releasing capabilities and we proved that CRC cell-released EVs have a miRNA-independent effect on fibroblast proliferation and activation.
Mechanisms Affecting Physical Aging and Swelling by Blending an Amphiphilic Component
Authors: Huang Shifen , Zhang Yiming , Wang Chenhong , Xia Qinghua , Saif Ur Rahman Muhammad , Chen Hao , Han Charles , Liu Ying , Xu Shanshan
Published: February 2022

Polymer blending is a promising method to overcome stability obstacles induced by physical aging and swelling of implant scaffolds prepared from amorphous polymers in biomedical application, since it will not bring potential toxicity compared with chemical modification. However, the mechanism of polymer blending still remains unclearly explained in existing studies that fail to provide theoretical references in material R&D processes for stability improvement of the scaffold during ethylene oxide (EtO) sterilization, long-term storage, and clinical application. In this study, amphiphilic poly(ethylene glycol)-co-poly(lactic acid) (PELA) was blended with amorphous poly(lactic-co-glycolic acid) (PLGA) because of its good miscibility so as to adjust the glass transition temperature (Tg) and hydrophilicity of electrospun PLGA membranes. By characterizing the morphological stability and mechanical performance, the chain movement and the glass transition behavior of the polymer during the physical aging and swelling process were studied. This study revealed the modification mechanism of polymer blending at the molecular chain level, which will contribute to stability improvement and performance adjustment of implant scaffolds in biomedical application.
Specific Impacts of Ketamine on Bladder Dysfunction and Associated Histological Alterations in Rats—A Time Course Validation through Transmission Electron Microscopy
Authors: Chung Shiu-Dong , Praveen Rajneesh Chellappan , Chen Kuo-Chiang , Tai Huai-Ching , Chang Meng-Lin , Tseng Xiao-Wen , Cheng Jai-Hong , Tsai Wei-Kung , Chiang Han-Sun , Wu Yi-No
Published: February 2022

This study explored the specific effects of ketamine on bladder function followed by a sequence of histological changes in a rat bladder at fixed time course intervals. The rats were grouped into normal control and experimental animals, and ketamine (100 mg/kg/day) was administrated to the experimental animals for 2, 4, and 8 weeks, respectively; similarly, the control animals received saline. All animals were evaluated for bladder function and histological responses to the treatment. Ultrastructural changes were observed by transmission electron microscopy (TEM). The results showed progressive bladder dysfunctions with hyperactive bladder conditions according to the time course and frequency of exposure to ketamine. Significantly, decreased inter contraction intervals, residual urine volume, peak micturition pressure, and increased micturition frequency were observed. Bladder histology results revealed substantial inflammation and comprehensive submucosa edema in week 2 and 4 rats along with fibrosis and significant bladder detrusor hypertrophy in week 8 rats. TEM analysis revealed bladder wall thickening, deformed blood vessels, detrusor hypertrophy, wobbled gap junction, and barrier dysfunction at different time course levels in experimental animals. These results provided a profound knowledge about the prognosis and step-by-step pathophysiology of the disease, which might help in developing new therapeutic interventions.
The Mitochondrial Epigenome: An Unexplored Avenue to Explain Unexplained Myopathies?
Authors: Mposhi Archibold , Liang Lin , Mennega Kevin P. , Yildiz Dilemin , Kampert Crista , Hof Ingrid H. , Jellema Pytrick G. , de Koning Tom J. , Faber Klaas Nico , Ruiters Marcel H. J. , Niezen-Koning Klary E. , Rots Marianne G.
Published: February 2022

Mutations in either mitochondrial DNA (mtDNA) or nuclear genes that encode mitochondrial proteins may lead to dysfunctional mitochondria, giving rise to mitochondrial diseases. Some mitochondrial myopathies, however, present without a known underlying cause. Interestingly, methylation of mtDNA has been associated with various clinical pathologies. The present study set out to assess whether mtDNA methylation could explain impaired mitochondrial function in patients diagnosed with myopathy without known underlying genetic mutations. Enhanced mtDNA methylation was indicated by pyrosequencing for muscle biopsies of 14 myopathy patients compared to four healthy controls, at selected cytosines in the Cytochrome B (CYTB) gene, but not within the displacement loop (D-loop) region. The mtDNA methylation patterns of the four healthy muscle biopsies were highly consistent and showed intriguing tissue-specific differences at particular cytosines with control skin fibroblasts cultured in vitro. Within individual myopathy patients, the overall mtDNA methylation pattern correlated well between muscle and skin fibroblasts. Despite this correlation, a pilot analysis of four myopathy and five healthy fibroblast samples did not reveal a disease-associated difference in mtDNA methylation. We did, however, detect increased expression of solute carrier family 25A26 (SLC25A26), encoding the importer of S-adenosylmethionine, together with enhanced mtDNA copy numbers in myopathy fibroblasts compared to healthy controls. To confirm that pyrosequencing indeed reflected DNA methylation and not bisulfite accessibility, mass spectrometry was employed. Although no myopathy-related differences in total amount of methylated cytosines were detected at this stage, a significant contribution of contaminating nuclear DNA (nDNA) was revealed, and steps to improve enrichment for mtDNA are reported. In conclusion, in this explorative study we show that analyzing the mitochondrial genome beyond its sequence opens novel avenues to identify potential molecular biomarkers assisting in the diagnosis of unexplained myopathies.
Design, Synthesis and Structure-Activity Relationship Studies of Meridianin Derivatives as Novel JAK/STAT3 Signaling Inhibitors
Authors: Zhang Jian-Qiang , Li Rui , Dong Xue-Yang , He Na , Yin Rui-Juan , Yang Meng-Ke , Liu Jie-Yu , Yu Ri-Lei , Zhao Chen-Yang , Jiang Tao
Published: February 2022

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling is an attractive therapeutic target for tumor therapy. Herein, forty-eight novel meridianin derivatives were designed and synthesized, and their antitumor activity was evaluated in vitro both for activity optimization and structure–activity relationship (SAR) study. The results indicated that most derivatives exhibited significantly improved antitumor activity, especially for compound 6e. The compound 6e contains an isothiouronium linked by an alkyl chain consisting of six carbon atoms with IC50 ranging from 1.11 to 2.80 μM on various cancer cell lines. Consistently, the 6e dose dependently induced the apoptosis of A549 and DU145 cells, in which STAT3 is constitutively active. Western blotting assays indicated that the phosphorylation levels of JAK1, JAK2 and STAT3 were inhibited by 6e at 5 μM without significant change in the total STAT3 level. Moreover, 6e also suppressed the expression of STAT3 downstream genes, including c-Myc, Cyclin D1 and Bcl-XL at 10 μM. An additional in vivo study revealed that 6e at the dose of 10 mg/kg could potently inhibit the DU145 xenograft tumor without obvious body weight loss. These results clearly indicate that 6e could be a potential antitumor agent by targeting the JAK/STAT3 signaling pathway.
Metformin’s Mechanism of Action Is Stimulation of the Biosynthesis of the Natural Cyclic AMP Antagonist Prostaglandylinositol Cyclic Phosphate (Cyclic PIP)
Authors: Wasner Heinrich K.
Published: February 2022

Metformin is the leading drug for treating type 2 diabetics, but the mechanism of action of metformin, despite some suggested mechanisms such as the activation of the AMP-kinase, is largely unknown. Among its many positive effects are the reduction of blood glucose levels, the inhibition of cyclic AMP synthesis, gluconeogenesis and an increase in sensitivity to insulin. Recent studies have described the natural antagonist of cyclic AMP, prostaglandylinositol cyclic phosphate. Synthesis of cyclic PIP is stimulated in all organs by hormones such as insulin and also by drugs such as metformin. Its primary action is to trigger the dephosphorylation of proteins/enzymes, phosphorylated on serine/threonine residues. Cyclic PIP triggers many of the regulations requested by insulin. The parallels between the beneficial effects of metformin and the regulations triggered by cyclic PIP suggest that the mechanism of action of this key drug may well be explained by its stimulation of the synthesis of cyclic PIP.
Mosquitoes Larvicidal Activity of Ocimum kilimandscharicum Oil Formulation under Laboratory and Field-Simulated Conditions
Authors: Ochola John Bwire , Mutero Clifford Maina , Marubu Rose Muthoni , Haller Barbara Frei , Hassanali Ahmed , Lwande Wilber
Published: February 2022

Mosquitoes are vectors of many severe diseases, including malaria, yellow as well as dengue fever, and lymphatic filariasis. The use of synthetic chemical insecticides for mosquito control has been associated with resistance development and detrimental human, and ecological effects. For a safer alternative, the emulsified Ocimum kilimandscharicum oil formulation was evaluated for its larvicidal activity. The oil was analyzed by GC and GC/MS. The formulations were evaluated against third instar mosquito larvae in the laboratory and later compared with Bacillus thuringiensis subsp. israelensis against An. gambiae under field-simulated conditions. Thirty-nine compounds were identified in the oil, the main ones being D-camphor (36.6%) and limonene (18.6%). The formulation showed significant larval mortalities against An. gambiae and An. arabiensis larvae with LC50 of 0.07 and 0.31 ppm, respectively, at 24 h. Under the field-simulated trial, within 24 h, the formulation showed 98% mortality while Bti had achieved 54%. On day three, it caused 100% mortality while Bti achieved 76.5%. The high bioactivity and sublethal toxic effects to offspring of treated mosquito larvae, in terms of disruption of larval morphological aspects, suggest the high potential of the formulation as a botanical larvicide. The formulation, thus, may provide a valuable alternative for the effective and eco-friendly control of disease vectors.
Comparative Screening of Mexican, Rwandan and Commercial Entomopathogenic Nematodes to Be Used against Invasive Fall Armyworm, Spodoptera frugiperda
Authors: Fallet Patrick , De Gianni Lara , Machado Ricardo A. R. , Bruno Pamela , Bernal Julio S. , Karangwa Patrick , Kajuga Joelle , Waweru Bancy , Bazagwira Didace , Degen Thomas , Toepfer Stefan , Turlings Ted C. J.
Published: February 2022

The fall armyworm (FAW), Spodoptera frugiperda Smith (Lepidoptera: Noctuidae) is an important pest of maize originating from the Americas. It recently invaded Africa and Asia, where it causes severe yield losses to maize. To fight this pest, tremendous quantities of synthetic insecticides are being used. As a safe and sustainable alternative, we explore the possibility to control FAW with entomopathogenic nematodes (EPN). We tested in the laboratory whether local EPNs, isolated in the invasive range of FAW, are as effective as EPNs from FAW native range or as commercially available EPNs. This work compared the virulence, killing speed and propagation capability of low doses of forty EPN strains, representing twelve species, after placing them with second-, third- and sixth-instar caterpillars as well as pupae. EPN isolated in the invasive range of FAW (Rwanda) were found to be as effective as commercial and EPNs from the native range of FAW (Mexico) at killing FAW caterpillars. In particular, the Rwandan Steinernema carpocapsae strain RW14-G-R3a-2 caused rapid 100% mortality of second- and third-instar and close to 75% of sixth-instar FAW caterpillars. EPN strains and concentrations used in this study were not effective in killing FAW pupae. Virulence varied greatly among EPN strains, underlining the importance of thorough EPN screenings. These findings will facilitate the development of local EPN-based biological control products for sustainable and environmentally friendly control of FAW in East Africa and beyond.
Immune Checkpoint Blockade in Lung Carcinoids with Aggressive Behaviour: One More Arrow in Our Quiver?
Authors: Di Molfetta Sergio , Feola Tiziana , Fanciulli Giuseppe , Florio Tullio , Colao Annamaria , Faggiano Antongiulio ,   NIKE Group
Published: February 2022

Lung carcinoids are well-differentiated and low-/intermediate-grade neuroendocrine neoplasms of the lung. Given their relative rarity, and the paucity of data available from prospective studies, no global consensus exists on the systemic treatment of these tumours. In recent years, immune checkpoint inhibitors have revolutionized cancer management and are under evaluation in patients with diverse types of neuroendocrine neoplasms. The aim of this narrative review is to analyse all available data for the use of approved immune checkpoint inhibitors in patients with lung carcinoids. We performed an extensive search for relevant data sources and found five published articles, one meeting abstract, and nine registered clinical trials indicating a growing interest of researchers in this field, and providing preliminary evidence of efficacy for combined nivolumab plus ipilimumab and durvalumab plus tremelimumab regimens in the treatment of advanced and/or metastatic lung carcinoids.
Telerehabilitation for Managing Daily Participation among Breast Cancer Survivors during COVID-19: A Feasibility Study
Authors: Loubani Khawla , Schreuer Naomi , Kizony Rachel
Published: February 2022

We aimed to examine the feasibility and impact of a short-term occupation-based telerehabilitation intervention (Managing Participation with Breast Cancer (MaP-BC)) on daily participation, health-related quality-of-life, and breast-cancer-related symptoms and understand women’s perspectives regarding strategies to manage daily participation and symptoms during COVID-19 pandemic. A mixed-methods study (single-arm pre–post with a qualitative component) included 14 women after their primary medical treatment for breast cancer. Women received six weeks of occupation-based intervention using a video-communication. Sessions focused on identifying functional goals and training strategies to manage daily participation. The primary outcome was perceived performance and satisfaction with meaningful activities by the Canadian Occupational Performance Measure (COPM). Secondary outcomes were participation in the Activity Card Sort (ACS), upper-extremity functioning of Disability Arm Shoulder Hand, self-reported symptom severity, executive-functioning, health-related quality of life, and a question regarding strategies used to manage daily participation. Women significantly improved their daily participation in meaningful activities in the COPM, most ACS activity domains, self-reported executive functioning, and health-related-quality-of-life. Qualitative findings revealed three main themes: (1) daily life under the threats of breast cancer and COVID-19, (2) women’s own strategies to overcome challenges, and (3) contribution of the MaP-BC. Providing telerehabilitation during the COVID-19 pandemic is feasible and successful in improving women’s daily participation after breast cancer.
Complications and Frequency of Surgical Treatment with AO-Type Hook Plate in Shoulder Trauma: A Retrospective Study
Authors: Lee Seung-Jin , Eom Tae-Won , Hyun Yoon-Suk
Published: February 2022

We investigated the complications and frequency of hook plate fixation in patients with shoulder trauma. We reviewed 216 cases of hook plate fixation use at our hospital between January 2010 and May 2020. Finally, we included 76 cases of acute distal clavicle fracture (DCF) and 84 cases of acute acromioclavicular joint dislocation (ACD). We investigated all complications after hook plate use, bony union in the DCF group, and reduction loss in the ACD group. We defined painful shoulder stiffness (PSS) as aggravating resting pain with stiff shoulder, and pain on shoulder elevation (PSE) as continued shoulder pain on elevation without PSS before plate removal. PSS was managed with intra-articular steroid injections or manipulation with or without arthroscopic capsular release (ACR). PSS occurred in 36 and 33 cases of DCF and ACD, respectively. PSE occurred in 17 of 76 fractures and 13 of 84 dislocations. However, no iatrogenic rotator cuff injury was verified by magnetic resonance imaging in patients with PSS or PSE. Subacromial erosion in patients with hook plate fixation should be considered a sequela and not a complication because it is unavoidable in surgery with an AO-type hook plate. The most common complication was PSS, followed by PSE.
Influence of Bone-Level Dental Implants Placement and of Cortical Thickness on Osseointegration: In Silico and In Vivo Analyses
Authors: Gil Javier , Sandino Clara , Cerrolaza Miguel , Pérez Román , Herrero-Climent Mariano , Rios-Carrasco Blanca , Rios-Santos Jose Vicente , Brizuela Aritza
Published: February 2022

The purpose of this research is to study the biomechanical response of dental implants in bone-level type locations, 0.5 mm above and below the bone level. In addition, the influence of the thickness of the cortical bone on osseointegration is determined due to the mechanical loads transfer from the dental implant to the cortical and trabecular bone. The thicknesses studied were 1.5 mm and 2.5 mm. Numerical simulations were performed using a finite element method (FEM)-based model. In order to verify the FEM model, the in silico results were compared with the results obtained from a histological analysis performed in an in vivo study with 30 New Zealand rabbits. FEM was performed using a computerized 3D model of bone-level dental implants inserted in the lower jawbone with an applied axial load of 100 N. The analysis was performed using different distances from the bone level and different thicknesses of cortical bone. The interface area of bone growth was evaluated by analyzing the bone–implant contact (BIC), region of interest (ROI) and total bone area (BAT) parameters obtained through an in vivo histological process and analyzed by scanning electron microscopy (SEM). Bone-level implants were inserted in the rabbit tibiae, with two implants placed per tibia. These parameters were evaluated after three or six weeks of implantation. FEM studies showed that placements 0.5 mm below the bone level presented lower values of stress distribution compared to the other studied placements. The lower levels of mechanical stress were then correlated with the in vivo studies, showing that this position presented the highest BIC value after three or six weeks of implantation. In this placement, vertical bone growth could be observed up the bone level. The smallest thickness of the study showed a better transfer of mechanical loads, which leads to a better osseointegration. In silico and in vivo results both concluded that the implants placed 0.5 mm below the cortical bone and with lower thicknesses presented the best biomechanical and histological behavior in terms of new bone formation, enhanced mechanical stability and optimum osseointegration.
Proposal of Quick Diagnostic Criteria for Disseminated Intravascular Coagulation
Authors: Wada Hideo , Yamamoto Akitaka , Tomida Masaki , Ichikawa Yuhuko , Ezaki Minoru , Masuda Jun , Yoshida Masamichi , Fukui Shunsuke , Moritani Isao , Inoue Hidekazu , Shiraki Katsuya , Suzuki Kei , Imai Hiroshi , Shimaoka Motomu , Shimpo Hideto
Published: February 2022

Background. The diagnostic criteria for disseminated intravascular coagulation (DIC) vary and are complicated and the cut-off values are different. Simple and quick diagnostic criteria for DIC are required in physicians for critical care. Material and methods. Platelet counts, prothrombin time–international normalized ratio (PT-INR) and D-dimer levels were examined in 1293 critical ill patients. Adequate cut-off values of these parameters were determined and a quick DIC score using these biomarkers was proposed. The quick DIC score was evaluated using a receiver operating characteristic (ROC) analysis. Results. Using the Japanese Ministry of Health, Labor and Welfare diagnostic criteria, 70 and 109 patients were diagnosed with DIC and pre-DIC, respectively. The ROC analysis of factors difference between DIC and non-DIC, revealed the following cut-off values: PT-INR, 1.20; platelet count, 12.0 × 1010/L and D-dimer, 10.0 μg/mL. Based on the above results, the quick DIC score system was proposed. All patients with DIC had a quick DIC score of 3, 4 or 5, and 85.3% of the patients with pre-DIC had a quick DIC score of ≥3 points. All patients with pre-DIC had a score of ≥2 points. In the ROC analysis, the area under the curve was 0.997 for DIC vs. non-DIC, and 0.984 for pre-DIC + DIC vs. non-DIC, and the cut-off value was 3 points for DIC and 2 points for DIC + pre-DIC. The quick DIC scores of non-survivors were significantly higher than those of survivors. Conclusions. The Quick DIC score system is a simple and useful tool that can be used for the diagnosis of DIC and pre-DIC. Further evaluation of the quick DIC score system in a large-scale study is required.
Clinical Characteristics, Management, and In-Hospital Mortality in Patients with Heart Failure with Reduced Ejection Fraction According to Sex and the Presence of Type 2 Diabetes Mellitus
Authors: Méndez-Bailón Manuel , Lorenzo-Villalba Noel , Jiménez-García Rodrigo , Hernández-Barrera Valentin , de Miguel-Yanes Jose María , de Miguel-Diez Javier , Muñoz-Rivas Nuria , Andrès Emmanuel , Lopez-de-Andrés Ana
Published: February 2022

Background: Type 2 diabetes mellitus (T2DM) is a risk factor for the development of heart failure with reduced ejection fraction (HFrEF). Aims: (1) To describe and compare the clinical characteristics and the use of diagnostic and therapeutic procedures among subjects hospitalized with HFrEF according to the presence of type 2 diabetes mellitus (T2DM) and sex; (2) to assess the effect of T2DM and sex on hospital outcomes among the patients hospitalized with HFrEF using propensity score matching (PSM); and (3) to identify which clinical variables were associated to in-hospital mortality (IHM) among the patients hospitalized with HFrEF and T2DM according to their sex. Methods: A retrospective cohort study from 2016 to 2019 using the Spanish National Hospital Discharge Database was conducted. The diagnosis and procedures were codified with the International Classification of Disease 10th version (ICD10). Subjects aged ≥ 40 with a primary diagnosis of HFrEF were included. We included those patients with a diagnosis of T2DM in any diagnosis position. The descriptive statistics used were total and relative frequencies (percentages), means with standard deviations, and medians with an interquartile range. To control the effect of confounding variables when T2DM patients and non-T2DM patients were compared, we matched the cohorts using PSM. Multivariable logistic regression models were used to identify which study variables independently affected the IHM among men and women with HF and T2DM. Also, this multivariable method was applied for sensitivity analyses to confirm the results of the PSM. Results: A total of 28,894 patients were included. T2DM was present in 39.59%. Women with T2DM more frequently had atrial fibrillation, valvular heart disease, anemia, dementia, depression, and hyponatremia than men with T2DM. However, men had more coronary heart disease, chronic renal disease, COPD, and obstructive sleep apnea. All the procedures were significantly more commonly used among men than women. Blood transfusion was the only procedure more frequently identified among women with T2DM. For the sensitivity analysis in patients with T2DM hospitalized with HFrEF, we confirmed the results of the PSM, finding that women had a 14% higher risk of dying in the hospital than men (OR 1.14; 95% CI 1.01–1.35). Obesity seemed to have a protective effect (OR 0.85; 95% CI 0.73–0.98) on the in-hospital morality. Conclusions: Subjects with diabetes are admitted for HFrEF and have a greater number of comorbidities than non-diabetics. Diabetic women have a higher mortality rate than men with diabetes and all the procedures evaluated were significantly more often used among men than women.
The Value of Fetal Heart Evaluation in Fetuses with Rare Congenital Lymphangiomas: A Cohort Study from a Single Tertiary Center across Two Decades (Years 1999–2020)
Authors: Kordjalik Paulina , Szmyd Bartosz , Karuga Filip Franciszek , Daszkiewicz Gabriela , Strzelecka Iwona , Respondek-Liberska Maria
Published: February 2022

Lymphangiomas are uncommon, benign (from a histopathology viewpoint) malformations of the lymphatic system with thin-walled vessels; however, these tumors may be dangerous for fetal or neonatal life. They are observed in 1:6000 newborns at birth and in 1:750 spontaneous abortions. We aimed to investigate the role of fetal echocardiography in the prognosis of lymphangioma. Selected data of 19,836 pregnant women studied between 1999 and 2020 were retrospectively analyzed. In total, 32 cases of lymphangioma meeting the following criteria were further analyzed: (1) ultrasound availability from the 1st trimester of pregnancy and (2) nuchal translucency ≤ 2.5 mm. Echocardiographic findings, karyotype, size, and location of the possible lesion were juxtaposed with the clinical follow-up. The statistical analysis was performed using Statistica 13.1 software (StatSoft, Tulsa, OK, USA). Lymphangioma in the analyzed material coexisted with abnormalities in fetal echo in 78% (n = 25) of cases, especially: heart defect in 50% (n = 16) and with normal heart structure with functional changes in 28% (n = 9). Karyotype was available in 50% of the analyzed cases (n = 16). Normal cytogenetic results were observed in 62.5% (n = 10) of cases. In the remaining cases, the following were observed: Turner Syndrome: 25% (n = 4) and Down Syndrome 12.5% (n = 2). The rate of alive newborns was significantly higher among fetuses with isolated lymphangioma in comparison to those with lymphangioma associated with abnormal ECHO examination: 38.46% (n = 5) vs. 15.38% (n = 2; p = 0.037). Abnormal ECHO exam was a poor prognostic sign for fetuses with lymphangioma; therefore, we think it is important to refer these cases for detailed echocardiography in tertiary centers. Moreover, it should be highlighted that in all lymphangioma cases there was an indication to perform the karyotype assessment, as there was a high risk of aneuploidy.
Cutting-Edge Research Trends in Colorectal Disease
Authors: Crippa Jacopo , Altomare Donato F. , Spinelli Antonino
Published: February 2022

The scientific effort in improving colorectal disease treatment and outcomes has allowed for a continuous shift of burdens that were previously thought to be unassailable [...]
Mixed-Reality-Assisted Puncture of the Common Femoral Artery in a Phantom Model
Authors: Uhl Christian , Hatzl Johannes , Meisenbacher Katrin , Zimmer Lea , Hartmann Niklas , Böckler Dittmar
Published: February 2022

Percutaneous femoral arterial access is daily practice in a variety of medical specialties and enables physicians worldwide to perform endovascular interventions. The reported incidence of percutaneous femoral arterial access complications is 3–18% and often results from suboptimal puncture location due to insufficient visualization of the target vessel. The purpose of this proof-of-concept study was to evaluate the feasibility and the positional error of a mixed-reality (MR)-assisted puncture of the common femoral artery in a phantom model using a commercially available navigation system. In total, 15 MR-assisted punctures were performed. Cone-beam computed tomography angiography (CTA) was used following each puncture to allow quantification of positional error of needle placements in the axial and sagittal planes. Technical success was achieved in 14/15 cases (93.3%) with a median axial positional error of 1.0 mm (IQR 1.3) and a median sagittal positional error of 1.1 mm (IQR 1.6). The median duration of the registration process and needle insertion was 2 min (IQR 1.0). MR-assisted puncture of the common femoral artery is feasible with acceptable positional errors in a phantom model. Future studies should aim to measure and reduce the positional error resulting from MR registration.