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In August 2018, the president of the World Bank noted that "'Human capital'-the potential of individuals-is going to be the most important long-term investment any country can make for its people's future prosperity and quality of life". Nevertheless, leaders and practitioners in academic science and medicine continue to be unaware of and poorly educated about the nature, extent, and impact of barriers to full participation of women and minorities in science and medicine around the world. This lack of awareness and education results in failures to fully mobilise the human capital of half the population and limits global technological and medical advancements. The chronic lack of recruitment, promotion, and retention of women in science and medicine is due to systemic, structural, organisational, institutional, cultural, and societal barriers to equity and inclusion. These barriers must be identified and removed through increased awareness of the challenges combined with evidence-based, data-driven approaches leading to measurable targets and outcomes. In this Review, we discuss these issues and highlight actions that could achieve gender equality in science and medicine. We survey approaches and insights that have helped to identify and remove systemic bias and barriers in science and medicine, and propose tools that will help organisational change toward gender equality. We describe tools that include formal legislation and mandated quotas at national or large-scale levels (eg, gender parity), techniques that increase fairness (eg, gender equity) through facilitated organisational cultural change at institutional levels, and professional development of core competencies at individual levels. This Review is not intended to be an extensive analysis of all the literature currently available on achieving gender equality in academic medicine and science, but rather, a reflection on finding multifactorial solutions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives Association of Southeast Asian Nations (ASEAN) is among the hardest hit low-income and middle-income countries by diabetes. Innovative Care for Chronic Conditions (ICCC) framework has been adopted by the WHO for health system transformation towards better care for chronic conditions including diabetes. We conducted an umbrella review of systematic reviews on diabetes care components effectively implemented in the ASEAN health systems and map those effective care components into the ICCC framework.Design An umbrella review of systematic reviews and/or meta-analyses following JBI (Joanna Briggs Institute) guidelines.Data sources Health System Evidence, Health Evidence, PubMed and Ovid MEDLINE.Eligibility criteria We included systematic reviews and/or meta-analyses which focused on management of type 2 diabetes, reported improvements in measured outcomes and had at least one ASEAN member state in the study setting.Data extraction and synthesis Two reviewers independently extracted the data and mapped the included studies into the ICCC framework. A narrative synthesis method was used to summarise the findings. The included studies were assessed for methodological quality based on the JBI critical appraisal checklist for systematic reviews and research syntheses.Results 479 records were found of which 36 studies were included for the analysis. A multidisciplinary healthcare team including pharmacists and nurses has been reported to effectively support patients in self-management of their conditions. This can be supported by effective use of digital health interventions. Community health workers either peers or lay people with necessary software (knowledge and skills) and hardware (medical equipment and supplies) can provide complementary care to that of the healthcare staff.Conclusion To meet challenges of the increased burden of chronic conditions including diabetes, health policy-makers in the ASEAN member states can consider a paradigm shift in human resources for health towards the multidisciplinary, inclusive, collaborative and complementary team.

Abstract Fault ruptures induced by earthquakes pose a significant threat to constructions, particularly underground structures such as pile foundations. Among various foundation types, batter pile foundations are widely used due to their ability to resist inclined forces. To gain new insights into the response of batter pile groups to fault ruptures caused by earthquakes, this study investigates the deformation and failure mechanisms of batter pile groups due to the propagation of normal and reverse fault ruptures using 3D numerical modeling. An advanced hypoplastic constitutive model for clay, which accounts for small-strain stiffness, and a concrete damage plasticity (CDP) model are employed to simulate the soil and the batter pile foundation, respectively. Results show that following fault propagation, nearly 10% tilting and significant displacement occurred at the pile cap, indicating a total failure of the batter pile foundation. It was also observed that the piles bent towards the slipping direction of the hanging wall. Tensile damage to the pile foundation was notably more severe than compression damage. The most severely damaged regions were not only located at the joints between the piles and the pile caps but were also found along the pile shafts.

Abstract Little is known about how exclusive e-cigarette use affects exosomal microRNA (miRNA) expression, which is crucial in inflammation and disease processes like cancer. We compared exosomal miRNA profiles between exclusive e-cigarette users and non-users. We used plasma samples from 15 exclusive e-cigarette users and 15 non-users from the Population Assessment of Tobacco and Health (PATH) Wave 1 study (2013–2014) and sequenced miRNAs with Illumina NextSeq 500/550. We performed differential analyses using DESeq2 in R/Bioconductor, adjusting for race, and conducted gene enrichment analyses on target genes regulated by significant miRNAs. Further, molecular-based techniques using the miRNA mimics and inhibitors were applied for the validation of the expressions of the miRNAs in vitro. We identified four miRNAs that were upregulated in exclusive e-cigarette users compared to non-users: hsa-miR-100-5p, hsa-miR-125a-5p, hsa-miR-125b-5p, and hsa-miR-99a-5p, after adjusting for the confounding effects of race. However, none of the miRNAs remained statistically significant after controlling for the false discovery rate (FDR) at 5%. Subgroup analysis of White participants only identified four miRNAs (hsa-miR-100-5p, hsa-miR-125b-5p, hsa-miR-200b-3p, and hsa-miR-99a-5p) that were also upregulated in e-cigarette users with one miRNA hsa-miR-200b-3p remaining statistical significance after controlling for the FDR at 5%. GO enrichment analysis showed that these miRNAs are involved in processes like transcription regulation and cellular protein modification. KEGG pathway analysis indicated their involvement in cancer pathways, including small cell lung cancer, renal cell carcinoma, and signaling pathways (neurotrophin, ErbB, PI3K-Akt, FoxO, Hippo, MAPK, TGF-beta). Overexpression of hsa-miR-125b-5p promoted DNA damage in bronchial epithelial cells. These findings suggest an elevation of carcinogenic cellular signaling pathways in exclusive e-cigarette users.

Abstract Background Night shift work during pregnancy has been associated with differential DNA methylation in placental tissue, but no studies have explored this association in cord blood. We aimed to examine associations of maternal night shift work with cord blood DNA methylation. Methods A total of 4487 mother–newborn pairs from 7 studies were included. Maternal night shift work during pregnancy was ascertained via questionnaires and harmonized into “any” versus “no”. DNA methylation was measured in cord blood using the Illumina Infinium Methylation arrays. Robust linear regression models adjusted for relevant confounders were run in the individual cohorts, and results were meta-analyzed. Results Maternal night shift work during pregnancy ranged from 3.4% to 26.3%. Three CpGs were differentially methylated in relation to maternal night shift work during pregnancy at a false discovery rate adjusted P

Abstract Bladder cancer often recurs, necessitating innovative treatments to reduce recurrence. We investigated non-thermal plasma’s potential as a novel anti-cancer therapy, focusing on plasma-activated solution (PAS), created by exposing saline to non-thermal plasma. Our study aims to elucidate the biological effects of PAS on bladder cancer cell lines in vitro, as well as the combination with mitomycin C (MMC), using clinically relevant settings. PAS treatment exerts a potent cytotoxic effect through the production of intracellular reactive oxygen species, resulting in DNA damage and subsequent induction of G1 cell cycle arrest/senescence. This is induced via upregulation of cell cycle checkpoint signalling and DNA damage repair pathways using LC-M/MS-based phospho-proteomics. Importantly, combining PAS with MMC reveals a synergistic effect (Combination Index of 0.59–0.67), suggesting the potential of utilizing PAS in combination therapies. Our findings demonstrate PAS’s mode of action and suggest its potential as a promising treatment for bladder cancer, warranting further clinical studies.

Abstract Tyrosine-protein kinase Src plays a key role in cell proliferation and growth under favorable conditions, but its overexpression and genetic mutations can lead to the progression of various inflammatory diseases. Due to the specificity and selectivity problems of previously discovered inhibitors like dasatinib and bosutinib, we employed an integrated machine learning and structure-based drug repurposing strategy to find novel, targeted, and non-toxic Src kinase inhibitors. Different machine learning models including random forest (RF), k-nearest neighbors (K-NN), decision tree, and support vector machine (SVM), were trained using already available bioactivity data of Src kinase targeting compounds. The performance evaluation of these models demonstrated SVM as the best model, which was further utilized to shortlist 51 highly potent compounds by screening an FDA-approved library of 1040 drugs. Molecular docking and molecular dynamic simulation were subsequently employed to evaluate the binding affinity and stability of the proposed compounds. Orlistat, acarbose and afatinib were identified as the potent leads, demonstrating stable conformations and stronger interactions, validated by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (RoG), and hydrogen bond analyses. Molecular Mechanics/Generalized Born Surface Area (MMGBSA) analysis validated their binding affinities by providing comparably lower binding free energies for orlistat (− 33.4743 ± 3.8908), acarbose (− 19.5455 ± 5.4702), and afatinib (− 36.4944 ± 5.4929) than the control, dasatinib (− 13.7785 ± 5.8058). Finally, toxicity analysis revealed orlistat and acarbose as the possible safer therapeutics by eliminating afatinib as it showed significant toxicity concerns. Our investigation supports the advance computational methods utilization in the field of drug discovery and suggest further experimental validation of proposed inhibitors of Src kinase for their safer use against inflammatory diseases. The ultimate aim of this study is to advance the development of effective treatments for inflammatory diseases, linked with Src overexpression.

Abstract Saffron (Crocus sativus L.) is the most expensive spice in the World, and Italy is among the major European producers. The study aims to improve value and recognition of high quality saffron by proposing a subdivision within the first quality category, according to ISO 3632 standards. The analysis of 125 saffron samples, collected from different Italian regions in 2021–2022 harvesting seasons, revealed that 95% of the samples met the first quality criteria, following ISO guidelines. Consequently, for the first quality samples, a differentiation into “premium”, “superior” and “high-quality” subcategories was proposed. Along with traditional methods, FT-NIR spectroscopy combined with chemometrics was employed for a comprehensive quality assessment. Discriminant and class-modelling approaches were developed to predict saffron quality subcategory. Best results were obtained by linear discriminant analysis models with accuracy in calibration (92.7%), cross-validation (86.4%) and prediction (87.0%). However, SIMCA modelling resulted more appropriate for class-modelling, confirming that none of the “premium” samples were misclassified as “high-quality” and vice-versa. The results support the inclusion of subcategories within ISO 3632 standards, thus refining the classification of saffron quality. Furthermore, the study emphasises the effectiveness of FT-NIR spectroscopy as a valuable tool for saffron quality assessment, with potential implications for industry standards and practices.

Abstract Phase-contrast micro-tomography ( $$\upmu$$ CT) with synchrotron radiation can aid in the differentiation of subtle density variations in weakly absorbing soft tissue specimens. Modulation-based imaging (MBI) extracts phase information from the distortion of reference patterns, generated by periodic or randomly structured wavefront markers (e.g., gratings or sandpaper). The two approaches have already found application for the virtual inspection of biological samples. Here, we perform high-resolution $$\upmu$$ CT scans of an unstained human placenta specimen, using MBI with both a 2D grating and sandpaper as modulators, as well as conventional propagation-based imaging (PBI). The 3D virtual representation of placenta offers a valuable tool for analysing its intricate branching villous network and vascular structure, providing new insights into its complex architecture. Within this study, we assess reconstruction quality achieved with all three evaluated phase-contrast methods. Both MBI datasets are processed with the Unified Modulated Pattern Analysis (UMPA) model, a pattern-matching algorithm. In order to evaluate the benefits and suitability of MBI for virtual histology, we discuss how the complexities of the technique influence image quality and correlate the obtained volumes to 2D techniques, such as conventional histology and X-ray fluorescence (XRF) elemental maps.

Abstract In this study, we synthesized two nanocomposites, cross-linked PVA/HKUST and PVA/ZIF-67, by integrating metal–organic frameworks (MOFs) into electrospun polyvinyl alcohol (PVA). Several characterization techniques including FTIR, XRD, ICP, SEM, TGA, UV–Vis, zeta potential, and N2 adsorption–desorption were employed. The adsorption performance of the composites for cefixime (CFX) removal was assessed under varying conditions such as MOF content, contact time, pH, initial CFX concentration, and temperature. ZIF-67 and HKUST contribute to the high adsorption efficiency of the composites by providing a porous structure with high surface area, facilitating interactions with CFX molecules, and enhancing the overall stability of the composite material in the removal process. The Langmuir isotherm model revealed a maximum adsorption capacity of 282.5 mg/g for PVA/HKUST and 211.4 mg/g for PVA/ZIF-67. Notably, CFX was rapidly removed within 50 min, demonstrating the high potential of these nanofibers in wastewater treatment. However, after six cycles, removal efficiencies declined from 88 to 74% for PVA/HKUST and from 85 to 59% for PVA/ZIF-67.

Abstract Soil is one of the most important reservoirs of antibiotic resistance, global threat that needs to be addressed with the One Health approach. Despite urban parks playing a fundamental role in urban ecosystems, the diffusion, maintenance, and human impact of antibiotic-resistance genes in this substrate are still poorly addressed. To fill in this gap, we adopted a molecular and culturomics approach to study antibiotic resistance in urban parks, accounting for the environmental matrix and the level of urbanization. A higher abundance of efflux-mediated mechanisms in undisturbed environments was observed, while antibiotic alteration or inactivation, and target replacement were more abundant in areas with a higher level of urbanization, also confirmed by significant correlations with anthropogenic features of the environmental matrix. Overall, this study highlights the crucial need to monitor antibiotic resistance in urban parks’ soil through a dual molecular and culturomics approach to fully understand and fight antibiotic resistance diffusion.

Abstract Aripiprazole (ARI) is an atypical antipsychotic which is a substrate of P-glycoprotein (P-gp), a transmembrane glycoprotein that plays a crucial role in eliminating potentially harmful compounds from the organism. ARI once-monthly (AOM) is a long-acting injectable form which improves treatment compliance. Genetic polymorphisms in ABCB1 may lead to changes in P-gp function, leading to individual differences in drug disposition. The present study aims to determine how the different variants of the three most prevalent SNPs of the ABCB1 gene affect plasma concentrations of ARI, of its active metabolite dehydroaripiprazole (DHA) and ARI/DHA ratio in patients under AOM treatment. The metabolizing state of the two main aripiprazole metabolizing enzymes (CYP2D6 and CYP3A4) were considered to specifically study the effect of P-gp on plasma concentrations of the parent compound and its active metabolite. The study found a clear relationship between the genotypes found for the different ABCB1 SNPs and the ARI/DHA ratio. Specifically, patients with GG genotype in G2677T have almost twice the ratio compared to TT genotype. Similarly, this increase is also found in C3435T with 1.4-fold and in C1236T with 1.6-fold for the same genotypes. Regarding haplotypes, significant differences were obtained between CC-GG-CC and TT-TT-TT patients, with an 87.9% higher ratio in patients with the CC-GG-CC haplotype. There was a clear trend towards lower ARI concentrations and higher DHA concentrations when the presence of mutated T alleles increases. The ABCB1 gene could be a good partner along with CYP2D6 and CYP3A4 genotyping in conjunction with monitoring ARI plasma concentrations.

Background and Study Aim. The issue of quality of life, physical activity, and health of students is becoming increasingly relevant in the context of the ongoing conflict in Ukraine. Daily shelling of cities and settlements for over two years may have significantly affected the quality of life of Ukrainian students. While students in Poland and Romania do not experience the direct impact of military actions, regional instability and mass migration processes may also influence their health and well-being. In this context, the aim of the study is to identify key trends and issues related to the quality of life and health of students in Ukraine, Poland, and Romania. Materials and Methods. The study involved students from Ukraine (n=193), Poland (n=40), and Romania (n=215). The SF-36 questionnaire, adapted into three languages: Ukrainian, Polish, and Romanian, was used to assess quality of life. Data collection was conducted online. The results were processed using PyCharm CE and specialized Python codes with relevant libraries. Cronbach's alpha coefficient (α Cronbach's = 0.765) was used to assess the internal consistency of the questionnaire responses. Factor analysis was conducted, with the number of factors (8) determined using the Kaiser criterion. The Mann-Whitney U test was used. Mean values, standard deviations, and percentage ratios were calculated. The significance level was set at 0.05. Results. Data analysis revealed significant differences in quality of life, physical activity, and health of students depending on the country and gender. Ukrainian students, affected by the ongoing conflict, showed a substantial decrease in mental health indicators. The average mental health score for Ukrainian female students was 25.42%, and for male students, it was 23.92%. This indicates high levels of stress and anxiety caused by constant threats and instability. Polish students are older than Romanian and Ukrainian students, with the highest indicators of height and weight. In Poland, women reported better mental health (58.67±15.94) compared to men (55.09±12.82). Men demonstrated better physical health indicators (50.50±6.96) compared to women (47.58±6.57). In Romania, men showed better results in the psychological health component (42.79±8.61) compared to women (39.67±8.70) and higher physical functioning scores. Conclusions. The results of the analysis highlight that the war in Ukraine significantly impacts the physical and mental health of Ukrainian students. The considerable cross-country differences in student health indicators underscore the need to consider the specific conditions and challenges faced by students in different countries. These differences are particularly important for developing targeted programs that can effectively support students in wartime conditions.

Current challenges regarding improving the materials used for implant production focus on improving mechanical strength, biocompatibility, bioactivity, and resistance to wear related to longer periods of prostheses use. The Polish company MEDGAL has patented a new type of bone implant coatings covered with a Si-DLC (silicon-carbon) layer. It is characterised by a carbon layer with a silicon fraction of +3/+5%. The process of chemical vapour deposition assisted by high-frequency plasma RF PACVD was used for production. The advantages of the method used are low process temperatures that do not cause structural changes, and thus there is no risk of intergranular corrosion. Carbon and carbon-silicon layers of high purity and homogeneity were obtained. Thanks to the use of a silicon particle, the proliferation of osteoblasts is stimulated. Silicon is also responsible for the increase in the expression of genes that stimulate the formation of ossification thanks to GMP-2 and may affect the stimulation of type I collagen synthesis.

Abstract Since therapeutic options are limited the utilization of prebiotics is suggested to prevent food allergies (FAs). Using an experimental peach allergy model we explored the effect of dietary fiber pectin, a high-methoxyl heteropolysaccharide, on the manifestation of FA. CBA/J mice were sensitized, subsequently orally boosted and provoked with peach peel extract. For dietary intervention, mice were fed a pectin containing diet before (primary-preventive) or after (secondary-preventive) sensitization. Non-treated allergic and sham-treated mice were fed a diet containing 20% cellulose. Fecal microbiota, humoral and intestinal immune cell responses were analyzed. Pectin remarkably affected the gut microbiota composition and diversity, promoting mainly the growth of Bacteroides. The frequency of mast cells, macrophages, and CD3+T cells in the lamina propria of the small intestine was reduced, whereas the frequency of B cells and CD4+T cell subpopulation was enhanced. Pectin intervention in the primary-preventive stetting significantly triggered serum IgA levels, whereas production of IgE and mMCPT-1 was reduced. Remarkably, in both settings peach allergen-specific IgG1/IgG2a ratio and specific IgE were significantly reduced to baseline. The data suggest, that dietary supplementation of pectin in both intervention approaches can diminish inflammatory responses and signs of allergic immune responses, accompanied by alteration of the gut microbiota composition.

Abstract Introduction Effective chronic disease management (CDM) is vital for addressing chronic disease challenges. Given the importance of ensuring pharmacists’ competence in CDM, interventions targeting knowledge, skills, and attitudes are essential. Therefore, a comprehensive and up-to-date study is needed to analyze these interventions’ effect and potential development. Categorizing the interventions based on the Effective Practice and Organization of Care (EPOC) taxonomy is essential for better informing policymakers. The objectives of this systematic review were to identify interventions to improve pharmacists’ competency in chronic disease management based on the EPOC taxonomy and summarize their effectiveness. Methods Following methods in the Cochrane Handbook, a systematic search was conducted up to April 2024 on MEDLINE and Scopus. The inclusion criteria were an intervention study with a randomized controlled trial (RCT) design published in English, targeting pharmacists, and measuring knowledge, skills, and attitudes in aspects of CDM. The risk of bias was assessed using Cochrane’s RoB 2 tool for either randomized or cluster-randomized trials. Findings are reported narratively and align with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results We included 11 RCT studies that focused on various aspects of CDM among community and hospital pharmacists. Implementation strategies and combined implementation strategies–delivery arrangements interventions were identified. Six implementation strategies interventions consistently yielded effective results, with scores ranging from 0.99 to 9.17 (p

Aim: Inflammatory indexes can relate to disease activity in ulcerative colitis (UC). This study aimed to evaluate whether the inflammatory indexes of neutrophil-lymphocyte ratio (NLR), C-reactive protein (CRP)-albumin ratio (CAR), CRP-lymphocyte ratio (CLR), and systemic immune-inflammation index (SIII) might predict the severity of mucosal inflammation in UC.Material and Methods: This retrospective case-control study included 184 UC patients and 101 healthy controls. The Mayo clinical score and Mayo endoscopic score were used for the clinical and endoscopic features of UC. Truelove and Richards’s method for the severity of mucosal inflammation determined the histological activity index (HAI).Results: The inflammatory index values, were higher in UC patients compared to the control group (p=0.007 for NLR, and p

Abstract Bovine spastic syndrome (SS) is a progressive, adult-onset neuromuscular disorder (NMD). SS is inherited but the mode of inheritance is unclear. The aim of this study was to characterize the phenotype and to identify a possible genetic cause of SS by whole-genome sequencing (WGS) and focusing on protein-changing variants. Seven affected unrelated Holstein cattle of both sexes were referred for SS at a mean age of 5.3 years (S.D.±1.1) showing intermittent spasm of the skeletal muscles of the pelvic girdle. Assuming monogenic recessive inheritance, analysis of the WGS data did not reveal any private variants common to all cases. Searching for homozygous rare variants considering each case individually, allowed the identification of a rare recessive likely pathogenic missense variant in TOR3A for one case with an allele frequency of 1.69% in a global Holstein population. In the remaining six SS cases, we identified seven potentially dominant de novo mutations or inherited alleles as private heterozygous, mostly missense, variants of uncertain significance involving seven different NMD candidate genes: MPEG1, LHX8, WHAMM, NGRN, TTN, ATP1A1, PCDH1. All eight candidate causal variants identified were predicted to be deleterious. This study describes for the first time WGS findings in confirmed cases of bovine SS and provides evidence for a heterogeneous genetic cause of SS in cattle.

Abstract We evaluate the evidence of cryptic speciation in Larimus breviceps, a species widely distributed in the western South Atlantic, from the Greater Antilles to Santa Catarina in Brazil. Mitochondrial (COI, Cyt b, and Control Region) and nuclear (IGF1 and Tmo-4C4) sequences were obtained from populations in the western South Atlantic. The analysis revealed two genetically distinct, sympatric lineages with no gene flow, with L. breviceps lineage II (LII) being closer to Larimus pacificus than to the L. breviceps lineage I (LI). The most recent common ancestor (TMRCA) for the L. breviceps LI and L. pacificus/L. breviceps LII clade dates from 12.3 Ma, whereas TMRCA for the L. pacificus and L. breviceps LII dates from 3.4 Ma, indicating that speciation processes may be related to the rise of the Isthmus of Panama. Despite these profound genetic differences, morphometric analyses found only subtle differences between lineages, with specimens of the LI being slightly larger than those of the LII, suggesting the existence of cryptic species. Within each lineage there is a pattern of panmixia within the study area. Therefore, we suggest that it is necessary a taxonomic revision of Larimus from the western Atlantic to validate the species status of such lineages.

S transfuzijo povezana volumska preobremenitev oz. TACO je najpogostejša respiracijska neželena transfuzijska reakcija (NTR). Pri TACO se med transfuzijo ali v 12 urah po njej pri dovzetnih bolnikih razvijeta kardiogeni pljučni edem in dihalna stiska zaradi volumske preobremenitve s tekočinami. Ogroženi so novorojenčki in dojenčki, starostniki, bolniki s srčnim popuščanjem, bolniki s hudo anemijo ter bolniki s pozitivno tekočinsko bilanco. Tvegana sta hitra transfuzija in večji volumen transfundiranih krvnih komponent. Bolnike s TACO zdravimo z dodajanjem kisika, intravenskimi diuretiki, nitrati in morfinskimi pripravki ter po potrebi z neinvazivnim ali invazivnim mehanskim predihavanjem. Čeprav je TACO v zadnjih letih v razvitem svetu najpogostejši vzrok za zbolevnost in za smrtni izid transfuzije, se ga pogosto spregleda in zato ne prijavi hemovigilančni službi. K temu prispevajo tako pomanjkljivo (pre)poznavanje simptomov in znakov TACO ter prekrivanje kliničnih slik pri kritično bolnih, kot tudi zahtevno razlikovanje od drugih dveh primarnih respiracijskih NTR: s transfuzijo povezane akutne okvare pljuč oz. TRALI in s transfuzijo povezane dispneje oz. TAD. S pregledom svetovne literature smo v članku povzeli najnovejša dognanja o patofiziologiji, klinični sliki in zdravljenju ter preprečevanju TACO. Podrobno opisujemo ISBT/IHN/AABB definicijo TACO iz leta 2018. Posebno pozornost smo namenili prikazu razlik med TACO, TRALI in TAD, ki bodo zdravnikom v pomoč pri diagnosticiranju. Za preprečevanje hudih posledic pri bolnikih je nujno potrebno znanje o preprečevanju, prepoznavanju in zdravljenju respiracijskih NTR. Enako velja za prijavljanje NTR hemovigilančni službi.

Abstract The circle of Willis (CoW) is a circular arrangement of arteries in the human brain, exhibiting significant anatomical variability. The CoW is extensively studied in relation to neurovascular pathologies, with certain anatomical variants previously linked to ischemic stroke and intracranial aneurysms. In an individual CoW, arteries might be absent (aplasia) or underdeveloped (hypoplasia, diameter < 1 mm). As the assessment of such variations is time-consuming and susceptible to subjectivity, robust automatic extraction of personalized CoW topology from time-of-flight magnetic resonance angiography (TOF-MRA) images would highly benefit large-scale clinical investigations. Previous work has sought to extract CoW topology from voxel-based semantic segmentation masks. However, hypoplastic arteries are challenging to recover in voxel-based segmentation. Instead, we propose using a complete CoW as an anatomical prior for extracting all possible CoW arteries as shortest paths between automatically identified anatomical landmarks, guided by automatically determined artery orientation vector fields. These fields are obtained using a scale-invariant and rotation-equivariant mesh-CNN-based model (SIRE). For a 3D TOF-MRA volume, a potentially overcomplete graph of the CoW is thus extracted in which each edge represents an artery. Subsequently, a binary Random Forest classifier labels each artery as normal or hypo-/aplastic. The model was optimized and validated using a data set of 351 3D TOF-MRA scans in a cross-validation setup. We showed that using a shortest path algorithm with a cost function based on local artery orientations results in continuous artery paths, even in hypoplastic cases. We tracked the correct path in the posterior communicating arteries in 70–74% of the cases, an artery that is known to pose challenges in voxel-based segmentation models. Our downstream artery path classifier obtained an average F1 score of 0.91, demonstrating the potential of our proposed framework to extract personalized CoW topology automatically.

Abstract Developmental delays have been associated with metabolic disturbances in children. Previous research in the childhood autism risk from genetics and the environment (CHARGE) case–control study identified neurodevelopment-related plasma metabolites in children, suggesting disturbances in the energy-related tricarboxylic acid (TCA) cycle and 1-carbon metabolism (1CM). Here, we investigated associations between children’s neurodevelopmental outcomes and their mothers’ plasma metabolite profiles in a subset of mother–child dyads from CHARGE, including those with autism spectrum disorder (ASD, n = 209), Down syndrome (DS, n = 76), idiopathic developmental delay (iDD, n = 64), and typically developed (TD, n = 185) controls. Multiple linear regression revealed associations between child neurodevelopmental outcomes and maternal plasma metabolites related to the TCA cycle, 1CM, and lipid metabolism. Despite profound metabolic disturbances in children with DS reported previously, few of these differences were observed in the mothers, which might reflect differences in gene dosage between children with DS and their euploid mothers. Notably differences in maternal metabolism related to ASD and iDD followed similar patterns of disturbance in previously reported metabolic signatures in children but were generally smaller in magnitude. Similar patterns of metabolic disturbances observed in mothers and their children with ASD or iDD could reflect shared genetic, mitochondrial, and/or environmental risk factors.

Abstract Genetic variants identified through genome-wide association studies (GWAS) are typically non-coding, exerting small regulatory effects on downstream genes. However, which downstream genes are ultimately impacted and how they confer risk remains mostly unclear. By contrast, variants that cause rare Mendelian diseases are often coding and have a more direct impact on disease development. Here we demonstrate that common and rare genetic diseases can be linked by studying how common disease-associated variants influence gene co-expression in 57 different tissues and cell types. We implemented this method in a framework called Downstreamer and applied it to 88 GWAS traits. We find that predicted downstream “genes” are enriched with Mendelian disease genes, e.g. key genes for height are enriched for genes that cause skeletal abnormalities and Ehlers–Danlos syndromes. 78% of these key genes are located outside of GWAS loci, suggesting that they result from complex trans regulation rather than being impacted by disease-associated variants in cis. Based on our findings, we discuss the challenges in reconstructing gene regulatory networks and provide a roadmap to improve the identification of these highly connected genes linked to common traits and diseases.

Abstract Background Multiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style functional data may help resolve variant classification disparities between populations, especially for Variants of Uncertain Significance (VUS). Methods We analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry from All of Us and the Genome Aggregation Database. Then, we incorporated clinically calibrated MAVE data into the Clinical Genome Resource’s Variant Curation Expert Panel rules to automate VUS reclassification for BRCA1, TP53, and PTEN. Results Using two orthogonal statistical approaches, we show a higher prevalence (p ≤ 5.95e − 06) of VUS in individuals of non-European-like genetic ancestry across all medical specialties assessed in all three databases. Further, in the non-European-like genetic ancestry group, higher rates of Benign or Likely Benign and variants with no clinical designation (p ≤ 2.5e − 05) were found across many medical specialties, whereas Pathogenic or Likely Pathogenic assignments were increased in individuals of European-like genetic ancestry (p ≤ 2.5e − 05). Using MAVE data, we reclassified VUS in individuals of non-European-like genetic ancestry at a significantly higher rate in comparison to reclassified VUS from European-like genetic ancestry (p = 9.1e − 03) effectively compensating for the VUS disparity. Further, essential code analysis showed equitable impact of MAVE evidence codes but inequitable impact of allele frequency (p = 7.47e − 06) and computational predictor (p = 6.92e − 05) evidence codes for individuals of non-European-like genetic ancestry. Conclusions Generation of saturation-style MAVE data should be a priority to reduce VUS disparities and produce equitable training data for future computational predictors.

Circovirus human is a new viral species that includes the human circovirus (HCirV), which has been linked to hepatitis in immunocompromised persons. We investigated prevalence of HCirV infection in 278 patients with hepatitis and 184 asymptomatic persons using real-time PCR and sequencing assays. HCirV viremia and sequences were found in 8 (2.9%) hepatitis patients and no asymptomatic patients. Alternate causes of hepatitis (hepatitis E and cholangitis) were clearly identifiable in 2 HCirV-infected patients. HCirV could not be ruled out as a contributor to hepatitis in the remaining 6 patients, 4 of whom were immunocompromised. Persistent infections were documented in 3 patients, but only 1 had relapsing hepatitis. One HCirV patient displayed symptoms of an infectious mononucleosis-like syndrome. Isolates clustered with known HCirV strains from France and China. HCirV-derived virus-like particles bound to PLC/PRF/5 and Hep-G2 human hepatoma cells but not to lung epithelial cells, indicating hepatic tropism.

Abstract The present study aimed to identify nutrients (UPLC-PDA-ESI-MS/MS, HPLC-RI method) and biological activities (antioxidant activity to reduce Fe3+ and ABTS·+, pancreatic lipase inhibitory effect, α-amylase, and α-glucosidase, anti-bacterial) of 14 highbush blueberries (Vaccinium corymbosum L.) cultivars (Northern type) as well as a principal component analysis (PCA) to assess the variation of these properties in the context of biodiversity. Most of the cultivars in this research have been first presented in this paper. Phytochemical profiling of the tested highbush blueberry fruit revealed 75 bioactive compounds, including 5 macroelements, 7 microelements, 7 monophosphate nucleotides, 15 anthocyanins, 1 phenolic acid, 14 flavonols, 11 essential amino acids, 8 non-essential amino acids, 2 sugars, 7 organic acids. The PCA showed that the profile and contents of the analyzed compounds as well as their anti-bacterial, antioxidant, anti-diabetic, and anti-obesity potentials depended significantly on the tested cultivars. Thus, the study provides comprehensive data on cultivar-specific biodiversity and correlations that can be used to design novel extracts rich in polyphenolic, amino acids, and/or minerals extracts from the selected cultivars of highbush blueberry as natural and alternative sources to fulfill the growing industry demand for supplements, pharmaceuticals, and nutraceutical products.

Abstract We use seismic ambient noise data from 724 publicly available broadband seismic stations across central Europe to create detailed phase velocity and attenuation maps of Rayleigh waves, focusing on short periods down to 3 s. We interpret these maps in terms of the underlying physical processes relevant to the nature of continental crust. Through a regionalized interpretation based on tectonic settings, we highlight the significant role of fluid-filled fractures in the attenuation of surface waves. Our findings indicate a close connection between the time elapsed since the last tectonic activity in the European crust and the attenuation coefficient values. Additionally, we observe a pronounced decrease in attenuation coefficient values at periods below 6 s. The anti-correlation between attenuation coefficient and phase velocity in recently active tectonic regions suggests that fluid-filled fractures are likely the dominant factor governing seismic attenuation in the European crust.

Background: Radiography is essential in dentistry for diagnosis and treatment planning, with two-dimensional imaging such as panoramic and periapical radiographs being commonly used. The advancement to three-dimensional imaging, specifically Cone Beam Computed Tomography (CBCT), provides more detailed visualization but remains underutilized due to limited availability and knowledge among dentists in Indonesia. Purpose: This research is aimed to determine the knowledge and experience of using 2D and 3D diagnostic imaging among dentists in Surabaya. Methods: This research is using an observational descriptive study with a cross-sectional design consisting of 100 dentists who are domiciled in Surabaya and registered with PDGI in Surabaya. Results: The result showed that dentists’ knowledge of 2D diagnostic imaging with a good category has a percentage of 18%, quite good category with 49% and poor category with 33%. Meanwhile, the dentists’ knowledge of 3D diagnostic imaging with a good category has a percentage of 9%, quite good category with 36% and poor category with 55%. Around 88% of respondents have referred their patients for panoramic and periapical radiographs, while only about 22% of dentists have referred their patients for CBCT examinations. Conclusion: The knowledge of dentists regarding 2D diagnostic imaging is quite good, while the knowledge of dentists regarding 3D diagnostic imaging is low. The majority of dentists in Surabaya often refer their patients for panoramic and periapical radiographic examinations compared to referring them for CBCT examinations.

Abstract Candida albicans is a leading cause of fungal infections in immunocompromised patients. Management of candidemia relies on a few antifungal agents, with fluconazole being first line therapy. The emergence of fluconazole-resistant strains highlights the pressing need to improve our molecular understanding of the drug response mechanisms. By sequencing the 5’P mRNA degradation intermediates, we establish that co-translational mRNA decay occurs in C. albicans and characterize how in vivo 5´-3´ exonuclease degradation trails the last translating ribosome. Thus, the study of the 5’ Phosphorylated mRNA degradome (5PSeq) offers a simple and affordable way to measure ribosome dynamics and identify codon specific ribosome stalls in response to drugs and amino acid deprivation. Building upon this, we combine RNA-Seq and 5PSeq to study the early response of sensitive and resistant C. albicans isolates to fluconazole. Our results highlight that transcriptional responses, rather than changes in ribosome dynamics, are the main driver of Candida resistance to fluconazole.

Abstract Ultramicrotomy is a well-established technique that has been applied in biology and medical research to produce thin sections or a blockface of an embedded sample for microscopy. Recently, this technique has also been applied in materials science or micro- and nanotechnology as a sample preparation method for subsequent characterization. In this work, an application of ultramicrotomy for the cross-section preparation of an inkjet-printed multilayer structure is demonstrated. The investigated device is a capacitor consisting of three layers. The top and bottom electrodes are printed with silver nanoparticle ink and the dielectric layer with a ceramic nanoparticle/polymer ink. A 3D profilometer is initially used to study the surface morphology of the printed multilayer. The measurements show that both electrodes exhibit a coffee-ring effect, which results in an inhomogeneous layer structure of the device. To obtain precise 3D information on the multilayer, cross-sections must be prepared. Argon ion beam milling is the current gold standard to produce a single cross-section in good quality, however, the cross-section position within the multilayer volume is poorly defined. Moreover, the milling process requires a significant investment of time and resources. Herein, we develop an efficient method to realize repetitive cross-section preparation at well-defined positions in the multilayer volume. Repetitive cross-sections are exposed by trimming with an ultramicrotome (UM) and this blockface is subsequently transferred into a scanning electron microscope (SEM) for imaging. A combination of custom-modified UM and SEM specimen holders allows repeated transfer of the clamped multilayer sample between instruments without damage and with high positioning accuracy. This novel approach enhances the combination of an established ultramicrotome and a SEM for multilayer sample volume investigation. Thus, a comprehensive understanding of printed multilayer structures can be gained, to derive insights for optimization of device architecture and printing process.

Abstract In vitro embryo culture often falls short of mimicking the physiological dynamism occurring in the reproductive tract, prompting developmental plasticity in mammalian embryos with consequential genotypic and phenotypic deviations. Recent research highlights the potential of biological derivatives in in vitro culture to mitigate these effects, being the extracellular matrix (ECM) one of the most important components in retaining structural and biological signals derived from the native source tissue. Current bioengineering techniques could provide ECM-based biomaterials mimicking the native environment and offering optimal embryonic development. Rabbit oviducts (n = 24) were decellularized and solubilized to create tissue-specific ECM (OviECM) hydrogels. Following physicochemical characterization, these hydrogels were applied as coatings for the in vitro culture of two-cell embryos over 48 h, along with embryos cultured under In vitro control conditions (n = 218/group), which were subsequently transferred to recipient females. A subset of embryos was recovered on day 6 for transcriptomic analysis (n = 75–80/group), while the remaining embryos were used to assess implantation and birth rates. Rabbit weights were monitored over 20 weeks post-delivery, with blood tests conducted at weeks 8 and 20. Bayesian inference methods were used for statistical analysis. Differences were considered relevant if P ≥ 0.8 (80%). No differences in embryo development and morphology were detected between the OviECM coating and In vitro control conditions. However, embryos cultured on these coatings exhibited upregulation of pathways involved in antigen presentation and immune system activation, as well as, increased cellular response to external stimulus and intracellular protein transport. The implantation and live birth rates were significantly higher in the coating group than in the In vitro control group (30.8% vs. 26.1% and 21.2% vs. 18.1%, respectively). During the first 20 weeks of life, the animals from the coating group showed higher weights than the In vitro control group P0 > 0.8. The animals of both experimental groups showed normal blood parameters. Implementation of OviECM coatings allows for improving in vitro conditions and decreases postnatal phenotypic deviations after assisted reproductive technology (ART). This study could initiate a new embryo culture techniques era to guarantee that ART is utilized in the most efficient and safest possible practice.