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We present progress in utilizing a machine learning (ML) assisted optimization framework to study the trends in a parameter space defined by spectrally shaped, high-intensity, petawatt-class (8 J, 45 fs) laser pulses interacting with solid targets and give the first simulation-based overview of predicted trends. A neural network (NN) incorporating uncertainty quantification is trained to predict the number of hot electrons generated by the laser–target interaction as a function of pulse shaping parameters. The predictions of this NN serve as the basis function for a Bayesian optimization framework to navigate this space. For post-experimental evaluation, we compare two separate neural network (NN) models. One is based solely on data from experiments, and the other is trained only on ensemble particle-in-cell simulations. Reviewing the predicted and observed trends across the experiment-capable laser parameter search space, we find that both ML models predict a maximal increase in hot electron generation at a level of approximately 12%–18%; however, no statistically significant enhancement was observed in experiments. On direct comparison of the NN models, the average discrepancy is 8.5%, with a maximum of 30%. Since shot-to-shot fluctuations in experiments affect the observations, we evaluate the behavior of our optimization framework by performing virtual experiments that vary the number of repeated observations and the noise levels. Here, we discuss the implications of such a framework for future autonomous exploration platforms in high-repetition-rate experiments. [ABSTRACT FROM AUTHOR]

We describe the development and demonstration of a high-repetition-rate-capable dual-channel (DC) x-ray spectrometer designed for high-intensity laser–plasma experiments (≥ 1 × 1 0 21 W/cm2). The spectrometer, which operates at high repetition rates, is limited only by the refresh rate of targets and the camera's frame rate. It features two channels, each equipped with a flat highly oriented pyrolytic graphite (HOPG) crystal and a unique detector plane, allowing it to resolve two distinct x-ray bands: approximately 7–10 and 10–13 keV. Each detector plate carrier holds two slots for active (scintillators) or passive (imaging plates) x-ray detectors. We present the design and testing of the HR-DC-HOPG using both the COMET laser (10 J, 0.5 ps shot/4 min) at LLNL's Jupiter Laser Facility and the SCARLET laser (10 J, 30 fs shot/min) at Ohio State University. The results demonstrate the spectrometer's performance across various laser energies, target materials, pulse shapes, and detector types. [ABSTRACT FROM AUTHOR]

We present the development of a flexible tape-drive target system to generate and control secondary high-intensity laser-plasma sources. Its adjustable design permits the generation of relativistic MeV particles and x rays at high-intensity (i.e., ≥1 × 1018 W cm−2) laser facilities, at high repetition rates (>1 Hz). The compact and robust structure shows good mechanical stability and a high target placement accuracy (<4 μm RMS). Its compact and flexible design allows for mounting in both the horizontal and vertical planes, which makes it practical for use in cluttered laser-plasma experimental setups. The design permits ∼170° of access on the laser-driver side and 120° of diagnostic access at the rear. A range of adapted apertures have been designed and tested to be easily implemented to the targetry system. The design and performance testing of the tape-drive system in the context of two experiments performed at the COMET laser facility at the Lawrence Livermore National Laboratory and at the Advanced Lasers and Extreme Photonics (ALEPH) facility at Colorado State University are discussed. Experimental data showing that the designed prototype is also able to both generate and focus high-intensity laser-driven protons at high repetition rates are also presented. [ABSTRACT FROM AUTHOR]

The present study investigates the structural integrity of a wind turbine tower structure under axial compression, described as a tapered tubular structure. Initially, the NREL model of the 5 MW-net wind turbine model was adapted and then scaled down to simplify the numerical analysis and for the convenience of future experimental study. The analysis was conducted using the Finite Element Modelling software Abaqus. To ensure the validity of the FEM modelling, the benchmarking study is conducted by referring to previously published work. The case configuration was developed by varying the material properties of the tower (high, medium, and low carbon steels) and the material properties of the tower due to the effect of the site temperature. The results obtained show that high carbon steel has the best properties for use in wind turbine structures. At -80 °C, this is the temperature condition where AH32 material has the best properties.

In this paper, research and comparison of tensile and impact properties were conducted on several materials broadly categorized as Steel and Alloys at cryogenic temperature of 77 K or -196°C. Tensile and impact properties exhibit an inverse relationship due to the nature of metals, where if a material has high strength, its ductility will decrease, and if it has high ductility, its strength will decrease. Generally, cryogenic treatment will result in periodic strength enhancement of materials, but a significant reduction in ductility occurs when the temperature surpasses the ductile to brittle transition temperature (DBTT). However, some materials can be processed to achieve desired property advantages, such as high toughness, high ductility, or a balanced combination of ductility and toughness without significant reduction in either property.

The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.

Background/aims: This study examined the effects of a specially designed energy-restricted diet with alternate carbohydrate intake on body composition and cardiometabolic risk factors in overweight and obese adults. The aim was to assess whether the intervention could lead to significant weight loss, improve body composition, and reduce cardiometabolic risks., Methods: Sixty-five participants (34 women, 31 men) with an average BMI of 31.8 ± 9.1 kg/m 2 (women) and 34.1 ± 6.4 kg/m 2 (men) participated in a 14-week intervention. The diet included different days of carbohydrate intake and a 20% reduction in total daily energy consumption. Anthropometric measurements and biochemical parameters, including predictive indices of cardiometabolic risk, were determined at baseline and after the intervention., Results: The intervention resulted in a significant reduction in body weight (mean weight loss of 17%, p < 0.001), with 64.6% of participants achieving a weight loss of at least 10%. Muscle mass as a percentage of total body weight increased. Cardiometabolic improvements were observed in fasting blood glucose (from 5.4 to 4.9 mmol/L, p < 0.001) and LDL cholesterol (from 3.38 to 2.81 mmol/L, p < 0.001). Gender-specific differences were found, particularly in HDL-C, which decreased significantly in women ( p = 0.013), while there was a non-significant increase in men. Cardiometabolic indices, including the Visceral Adiposity Index (VAI) and the Cardiometabolic Index (CMI), also improved significantly., Conclusions: The alternate carbohydrate diet improved body composition, cardiometabolic health, and treatment adherence through metabolic flexibility. However, the short duration of this study and the lack of a control group suggest that further research is needed to assess long-term sustainability.

Phthalates are a family of synthetic chemicals commonly used as plasticizers for polyvinyl chloride-based polymers. They are used in a variety of commercial consumer products, including children's toys. Exposure to phthalates is associated with various adverse health effects, such as developmental and reproductive disorders, liver and kidney toxicity, etc. In the European Union, but also in the Republic of Serbia, restrictions have been imposed on the presence of seven phthalates in toys. In addition, the European Union has established the Rapid Alert System for Dangerous Non-Food Products (RAPEX) to protect consumers across borders by preventing or restricting the sale and use of non-food articles, including children's toys, that pose a significant health and safety risk. In this work, 118 samples of children's toys from the market of the Republic of Serbia were analysed for the presence of all seven restricted phthalates using the HPLC-DAD method. We also comprehensively analysed the RAPEX notifications of toys posing a chemical risk due to the presence of phthalates from 2012 to 2022. In total, 23.7% of the tested toy samples contained one or more phthalates above 0.1% w/w, which corresponds to the legal limit. DEHP was found above the limit in all non-compliant toy samples, followed by DBP, DINP, BBP and DIDP. DIBP and DNOP were not found in any of the samples. In general, phthalates were present in the tested samples in concentrations ranging from

Obesity is often accompanied by low-grade chronic inflammation and metabolic syndrome. It has been established that microbiota influences many physiological processes, including the development of obesity, and dysbiosis has been observed in obese individuals. In this study, we aimed to evaluate the impact of a new probiotic formulation, containing two probiotic strains and the bioactive compound octacosanol, on body weight, metabolic parameters, and concentrations of certain adipocytokines and appetite-regulating hormones in obese women. This double blind placebo-controlled supplementary intervention study included twenty-five women in the intervention group and twenty-three in the placebo group, and it lasted 12 weeks. Daily oral supplementation included 7 × 10 10 CFU of Lactiplantibacillus plantarum 299v (DSM9843), 5 × 10 9 CFU of Saccharomyces cerevisiae var. boulardii (DBVPG6763), and 40 mg of octacosanol or placebo. Body weight, metabolic parameters, adipocytokines, and appetite-regulating hormones were assessed before (T0) and after the intervention (T1). After the intervention, significantly lower median concentrations of CRP ( p = 0.005) and IL-6 ( p = 0.012) were measured in the intervention group than the baseline, while the median concentrations of ghrelin ( p = 0.026) and HDL-cholesterol ( p = 0.03) were significantly increased. The intervention group had lower CRP levels ( p = 0.023) and higher ghrelin levels ( p = 0.006) than the placebo group. Significant changes in BMI between groups were not observed. In summary, although the new probiotic formulation showed beneficial effects on IL-6, CRP, HDL, and ghrelin levels, its potential effects on regulating triglyceride, insulin, and glucose levels require further studies before the novel dietary intervention could be considered a useful adjuvant therapy and an effective strategy for the management of obesity and obesity-associated comorbidities.

Objective: This study evaluated the costs associated with four approaches to classifying endometrial cancer (EC), including histomorphological, histomorphological with ancillary immunohistochemical assays, histomolecular and selective molecular classification., Methods: Direct costs were determined per EC sample from the hospital's perspective. A budget impact analysis and sensitivity analysis were conducted to estimate the mean, minimum and maximum costs per sample and annual institutional costs in adjusted 2022 Canadian dollars. A provincial cost forecast was projected based on expected 2022 EC biopsies., Results: In 2018, our institution performed 190 EC biopsies. The mean cost per biopsy was $158 ($156-$212) for histomorphological classification, $384 ($360-$514) for histomorphological classification with immunohistochemistry and $1297 ($1265-1833) for histomolecular classification. Total annual institutional cost for histomorphological classification was $29,980 and $72,950 with immunohistochemistry. For histomolecular classification, the first year cost was $246,521, accounting for initial educational learning curve, and $233,461 thereafter, assuming a consistent number of biopsies per year. Targeted implementation of histomolecular classification among high-grade, p53 abnormal and/or MMR-deficient ECs (56% of cases) cost $169,688 in the first year and $162,418 annually thereafter. With a projected 3400 EC biopsies in Ontario in 2022, histomorphological classification would annually cost $537,078 and $1,305,677 with immunohistochemistry. Histomolecular classification would cost $4,410,203 in the first year and $4,176,737 annually once established. Selective molecular classification would lead to a cost of $3,044,178 in the first year and $2,913,443 thereafter., Conclusions: The study highlights the need for informed decision-making when implementing molecular classification in clinical practice, given the substantial incremental healthcare costs associated with these approaches., Competing Interests: Declaration of Competing Interest None., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

The interplay between genetic transformations, biochemical communications, and physical interactions is crucial in cancer progression. Metastasis, a leading cause of cancer-related deaths, involves a series of steps, including invasion, intravasation, circulation survival, and extravasation. Mechanical alterations, such as changes in stiffness and morphology, play a significant role in all stages of cancer initiation and dissemination. Accordingly, a better understanding of cancer mechanobiology can help in the development of novel therapeutic strategies. Targeting the physical properties of tumours and their microenvironment presents opportunities for intervention. Advancements in imaging techniques and lab-on-a-chip systems enable personalized investigations of tumor biomechanics and drug screening. Investigation of the interplay between genetic, biochemical, and mechanical factors, which is of crucial importance in cancer progression, offers insights for personalized medicine and innovative treatment strategies., Competing Interests: Authors BS and BD were employed by 199 Biotechnologies Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Javanmardi, Shahreza, Serwinski, Aref, Djordjevic and Moeendarbary.)

The remarkable contractility and force generation ability exhibited by cancer cells empower them to overcome the resistance and steric hindrance presented by a three-dimensional, interconnected matrix. Cancer cells disseminate by actively remodelling and deforming their extracellular matrix (ECM). The process of tumour growth and its ECM remodelling have been extensively studied, but the effect of the cellular tumour microenvironment (TME) has been ignored in most studies that investigated tumour-cell-mediated ECM deformations and realignment. This study reports the integration of stromal cells in spheroid contractility assays that impacts the ECM remodelling and invasion abilities of cancer spheroids. To investigate this, we developed a novel multilayer in vitro assay that incorporates stromal cells and quantifies the contractile deformations that tumour spheroids exert on the ECM. We observed a negative correlation between the spheroid invasion potential and the levels of collagen deformation. The presence of stromal cells significantly increased cancer cell invasiveness and altered the cancer cells' ability to deform and realign collagen gel, due to upregulation of proinflammatory cytokines. Interestingly, this was observed consistently in both metastatic and non-metastatic cancer cells. Our findings contribute to a better understanding of the vital role played by the cellular TME in regulating the invasive outgrowth of cancer cells and underscore the potential of utilising matrix deformation measurements as a biophysical marker for evaluating invasiveness and informing targeted therapeutic opportunities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023 Published by Elsevier Ltd.)

Several studies report the important role of an altered gut microbiota in the development of obesity, highlighting the potential use of probiotics in the treatment of obesity. The aim of this study is to investigate the effect of a novel probiotic approach on the expression of specific miRNAs and mRNAs associated with obesity in combination with the hypocholesterolemic octacosanol. Twenty overweight/obese women participated in a randomized, placebo-controlled, double-blind study and were randomly divided into two groups: the intervention group (daily one capsule containing Lactobacillus plantarum 299v (DSM9843), Saccharomyces cerevisiae var. boulardii , and 40 mg octacosanol; N = 12) and the placebo group (N = 8). Changes in lipid parameters and expression of miRNAs and mRNAs were assessed before (T0) and after the 12-week intervention (T1). After the intervention, the expression of miR-155-5p (9.38 ± 0.85 vs. 8.38 ± 1.06, p = 0.05) and miR-24-3p (3.42 ± 0.38 vs. 2.71 ± 0.97, p = 0.031) showed significant decreases in the intervention group when compared to the control group. At T1, the expression of miR-155-5p (8.69 ± 1.31 vs. 9.3 ± 0.85, p = 0.04), miR-125b-5p (5.41 ± 1.18 vs. 5.99 ± 1.36, p = 0.049), and TNF-α (10.24 ± 1.66 vs. 11.36 ± 1.12, p = 0.009) were significantly decreased in the intervention group. No changes in lipids and anthropometric parameters were observed. The novel probiotic approach had a positive effect on regulating the expression of certain miRNAs and mRNAs important for regulating inflammation and adipogenesis, which are essential for obesity onset and control.

Aims: Our understanding of dedifferentiated endometrial carcinoma (DEC), a rare and aggressive malignancy, mainly reflects undifferentiated carcinomas (UC) arising in the setting of low-grade endometrial cancer (DEC-LG). However, cases of UC arising in the setting of high-grade EC (DEC-HG) have been noted in the literature. Our knowledge of the genomics of DEC-HG is limited. To characterise the molecular landscape of DEC-HC, targeted genomic sequencing and immunohistochemical analysis was carried out on seven DEC-HG and four DEC-LG., Methods and Results: DEC-HG and DEC-LG, including undifferentiated and differentiated components, both showed a similar frequency and spectrum of mutations. ARID1A mutations were identified in 6/7 (86%) DEC-HG and 4/4 (100%) DEC-LG, while SMARCA4 mutations were present in 4/7 (57%) DEC-HG and in 1/4 (25%) DEC-LG. Concurrent SMARCA4/BRG1 protein loss by immunohistochemistry was observed in 3/4 and 1/1 SMARCA4 mutated DEC-HG and DEC-LG, respectively. Neither genomic alterations nor protein loss in SMARCB1/INI1 were observed in any of our cases. TP53 mutations were detected in 4/7 (57%) DEC-HG and in 2/4 (50%) DEC-LG, while mutation-pattern p53 immunohistochemistry expression was observed in 2/7 (29%) DEC-HG and none of the DEC-LG. MLH1 mutations were observed in 1/7 (14%) DEC-HG and 1/4 (25%) DEC-LG. MSH2 and MSH6 mutations were each detected in 1/7 (14%) DEC-HG, but neither was associated with corresponding loss of protein expression., Conclusion: The findings support expanding the definition of DEC to include DEC-HG, a previously under-recognised phenomenon with genomic similarities to DEC-LG., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Vascularization is driven by morphogen signals and mechanical cues that coordinately regulate cellular force generation, migration, and shape change to sculpt the developing vascular network. However, it remains unclear whether developing vasculature actively regulates its own mechanical properties to achieve effective vascularization. We engineered tissue constructs containing endothelial cells and fibroblasts to investigate the mechanics of vascularization. Tissue stiffness increases during vascular morphogenesis resulting from emergent interactions between endothelial cells, fibroblasts, and ECM and correlates with enhanced vascular function. Contractile cellular forces are key to emergent tissue stiffening and synergize with ECM mechanical properties to modulate the mechanics of vascularization. Emergent tissue stiffening and vascular function rely on mechanotransduction signaling within fibroblasts, mediated by YAP1. Mouse embryos lacking YAP1 in fibroblasts exhibit both reduced tissue stiffness and develop lethal vascular defects. Translating our findings through biology-inspired vascular tissue engineering approaches will have substantial implications in regenerative medicine.

Widespread neurodegeneration, enlargement of cerebral ventricles, and atrophy of cortical and hippocampal brain structures are classic hallmarks of Alzheimer's disease (AD). Prominent macroscopic disturbances to the cytoarchitecture of the AD brain occur alongside changes in the mechanical properties of brain tissue, as reported in recent magnetic resonance elastography (MRE) measurements of human brain mechanics. Whilst MRE has many advantages, a significant shortcoming is its spatial resolution. Higher resolution "cellular scale" assessment of the mechanical alterations to brain regions involved in memory formation, such as the hippocampus, could provide fresh new insight into the etiology of AD. Characterization of brain tissue mechanics at the cellular length scale is the first stepping-stone to understanding how mechanosensitive neurons and glia are impacted by neurodegenerative disease-associated changes in their microenvironment. To provide insight into the microscale mechanics of aging brain tissue, we measured spatiotemporal changes in the mechanical properties of the hippocampus using high resolution atomic force microscopy (AFM) indentation tests on acute brain slices from young and aged wild-type mice and the APP NL-G-F mouse model. Several hippocampal regions in APP NL-G-F mice are significantly softer than age-matched wild-types, notably the dentate granule cell layer and the CA1 pyramidal cell layer. Interestingly, regional softening coincides with an increase in astrocyte reactivity, suggesting that amyloid pathology-mediated alterations to the mechanical properties of brain tissue may impact the function of mechanosensitive astrocytes. Our data also raise questions as to whether aberrant mechanotransduction signaling could impact the susceptibility of neurons to cellular stressors in their microenvironment., Competing Interests: BS and BD were employed by 199 Biotechnologies Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hall, Lasli, Serwinski, Djordjevic, Sheridan and Moeendarbary.)

Aims: To report novel observations in five mesonephric-like adenocarcinomas (MLAs) of the female genital tract., Methods and Results: We report two endometrial MLAs in association with endometrioid carcinoma and atypical hyperplasia and three (one endometrial, two ovarian) cases with a sarcomatoid component (mesonephric-like carcinosarcoma). Pathogenic KRAS mutations, which are characteristic of MLA, were identified in all cases although interestingly, in one of the mixed carcinomas, this was confined to the endometrioid component. The concurrent MLA, endometrioid carcinoma and atypical hyperplasia components in one case harboured identical EGFR, PTEN and CCNE1 mutations, suggesting that the atypical hyperplasia gave rise to a Müllerian carcinoma with both endometrioid and mesonephric-like components. The carcinosarcomas all contained a component of MLA and a sarcomatous component with chondroid elements. In the ovarian carcinosarcomas, the coexisting epithelial and sarcomatous components shared some mutations including KRAS and CREBBP, suggesting that they are clonally related. Furthermore, in one case CREBBP and KRAS mutations detected in the MLA and sarcomatous components were also detected in an associated undifferentiated carcinoma component, suggesting that it was clonally related to the MLA and sarcomatous components., Conclusions: Our observations provide additional evidence that MLAs have a Müllerian origin and characterise mesonephric-like carcinosarcomas in which chondroid elements appear to be characteristic. In reporting these findings, we provide recommendations for distinction between a mesonephric-like carcinosarcoma and a MLA with a spindle cell component., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Cancer cell extravasation, a key step in the metastatic cascade, involves cancer cell arrest on the endothelium, transendothelial migration (TEM), followed by the invasion into the subendothelial extracellular matrix (ECM) of distant tissues. While cancer research has mostly focused on the biomechanical interactions between tumor cells (TCs) and ECM, particularly at the primary tumor site, very little is known about the mechanical properties of endothelial cells and the subendothelial ECM and how they contribute to the extravasation process. Here, an integrated experimental and theoretical framework is developed to investigate the mechanical crosstalk between TCs, endothelium and subendothelial ECM during in vitro cancer cell extravasation. It is found that cancer cell actin-rich protrusions generate complex push-pull forces to initiate and drive TEM, while transmigration success also relies on the forces generated by the endothelium. Consequently, mechanical properties of the subendothelial ECM and endothelial actomyosin contractility that mediate the endothelial forces also impact the endothelium's resistance to cancer cell transmigration. These results indicate that mechanical features of distant tissues, including force interactions between the endothelium and the subendothelial ECM, are key determinants of metastatic organotropism., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Coronavirus disease 2019 (COVID-19) is an acute respiratory disease associated with severe systemic inflammation. The optimal status of vitamins and microelements is considered crucial for the proper functioning of the immune system and necessary for successful recovery. Most patients with respiratory distress in COVID-19 are vitamin and microelement deficient, with vitamin D and Se deficiency being the most common. Anyway, various micronutrient supplements are widely and arbitrarily used for prevention or in the treatment of COVID-19. We aimed to summarise current knowledge about molecular and physiological mechanisms of vitamins (D, A, C, B 6 , B 9 and B 12 ) and microelements (Se, Zn, Cu and Fe) involved in the immune system regulation in consideration with COVID-19 pathogenesis, as well as recent findings related to their usage and effects in the prevention and treatment of COVID-19. In the early course of the pandemic, several, mainly observational, studies reported an association of some micronutrients, such as vitamin C, D and Zn, with severity reduction and survival improvement. Still, emerging randomised controlled trials showed no effect of vitamin D on hospitalisation length and no effect of vitamin C and Zn on symptom reduction. Up to date, there is evidence neither for nor against the use of micronutrients in the treatment of COVID-19. The doses that exceed the recommended for the general population and age group should not be used, except in clinical trials. Benefits of supplementation are primarily expected in populations prone to micronutrient deficiencies, who are, as well, at a higher risk of worse outcomes in COVID-19.

Objective: To define which oxidative stress markers could be used as diagnostic tools in the assessment of post-infarction heart failure (HF)., Methods: This observational study enrolled patients with HF that were divided into three subgroups (ejection fraction [EF] ≥ 50%; EF 40-49%; EF < 40%) and age- and sex-matched healthy control subjects. The plasma concentrations of advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances, catalase activity and free thiols were determined in all participants., Results: The study enrolled 81 patients with HF and 68 healthy control subjects. There were significant differences in the values ​​of oxidative stress markers between patients and controls. Oxidative stress parameters did not differ between the subgroups of patients, except for AOPP, which was significantly higher in the EF < 40% group. Univariate and multivariate logistic regression analyses showed an association between AOPP and HF in the EF ≥ 50% group, while receiver operating characteristic (ROC) curve analysis identified a cut-off value of 60.89 µmol/l for AOPP., Conclusions: Based on the ROC curve analysis of AOPP and the higher significance in the multivariate analyses for patients with EF ≥ 50%, these current results suggest that AOPP could be a useful additional tool in the assessment of post-infarction HF.

Melanoma is one of the most aggressive tumors, and in the setting of rising incidence and mortality, there is an urgent need to identify new prognostic markers. Toll-like receptors (TLRs), are aberrantly expressed in numerous cancers, including melanoma. TLR signaling provides a microenvironment that is involved in antitumor immune response, chronic inflammation, cancer cell proliferation and evasion of immune destruction. In the present study, we investigated whether single nucleotide polymorphisms (SNPs) in TLR3 and TLR4 genes are associated with clinicopathologic features, progression and survival of melanoma patients. The study was conducted on 120 melanoma patients. DNA extracted from peripheral blood was genotyped for TLR3 polymorphisms rs5743312 and rs3775291 (L412F) and TLR4 polymorphisms rs4986790 (D299G) and rs4986791 (T399I), by TaqMan Real-Time PCR Assays. Kaplan-Meier survival curves were compared by the log-rank test. TLR3 polymorphism L412F was associated with a higher mitotic index ( P  = 0.035). TLR4 D299G and T399I polymorphisms were associated with indicators of melanoma severity, nodal metastases ( P  = 0.005 and P  = 0.007, respectively) and advanced stage III ( P  = 0.005 and P  = 0.004, respectively). Cox regression analysis showed that the presence of tumor-infiltrating lymphocytes (TILs) predicted better overall survival (HR = 0.318; P  = 0.004). TLR4 T399I polymorphism was significantly associated with worse survival, P  = 0.025. The overall survival rates were significantly lower for patients carrying variant allele T of TLR4 T399I SNP (TC and TT genotypes combined) ( P  = 0.008, log-rank test), compared to wild-type genotype CC. Our findings indicate that TLR4 polymorphisms T399I (rs4986791) and D299G (rs4986790) could be potential prognostic and survival markers for melanoma patients., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Nuts and seeds are an indispensable part of the plant-based diet, which is becoming increasingly popular due to the evidence of their health benefits and contribution to sustainability and planetary health. Since the health effects of consuming nuts and seeds directly depend on their nutritional composition and consumed amount, it is essential to know the exact chemical composition of each nut and seed so that appropriate dietary interventions can be adequately planned. The present study aimed to examine the chemical composition of nuts and seeds obtained from the Serbian market and to highlight the similarities and differences in their nutritional composition. In twenty-four samples of nuts and seeds, the content of total lipids, including fatty acid profile, total proteins, including amino acid profile, total carbohydrates (sugars and fibers), phytosterols, and minerals were determined. Content of selected nutrients in grams (g) or milligrams (mg) of nuts and seeds was expressed in one portion (28 g) and as a percentage of contribution of Reference Intakes (% RI) and Dietary Reference Value (% DRV) for macronutrients and minerals, respectively. Some of the seed representatives appeared to be rich sources of essential omega-3 fatty acid, α-linolenic acid (ALA) (flax seed vs . walnut, 6.50 vs . 0.56 g per portion, respectively), dietary fibers (chia seed vs. raw almond, 10.6 vs. 3.4 g per portion, respectively), calcium (black sesame seed vs . almond roasted, 32.4% NRV vs . 8.1% NRV per portion, respectively), magnesium (hemp seed vs. Brazil nut, 38.3% NRV vs . 27.8% NRV per portion, respectively), and zinc (hemp seed vs. pine nut, 21.4% NRV vs. 17.6% NRV per portion, respectively). Our results highlighted the crucial role of seeds in the diet, especially as a better source of nutrients compared to nuts. Furthermore, it was seen that nuts and seeds are different and complementary in their composition. Thus, in order to meet the needs for certain nutrients for which nuts and seeds are used as dietary sources (essential fatty acids, minerals, dietary fibers), it would be beneficial to combine both nuts and seeds as a part of a healthy dietary pattern., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dodevska, Kukic Markovic, Sofrenic, Tesevic, Jankovic, Djordjevic and Ivanovic.)

Background: Coronavirus disease 2019 (COVID-19) profoundly affects the immune and hematopoietic systems with various degrees of reactive changes in the blood cell counts. Immuno-inflammatory indices are considered a simple and effective tool in the prediction of COVID-19 outcomes. We aimed to evaluate and compare the usefulness of leukocyte and platelet counts-based immuno-inflammatory indices on admission to hospital in predicting COVID-19 progression and mortality., Methods: A total of 945 patients were enrolled. In addition to blood cell counts, we assessed hemogram-derived immuno-inflammatory indices in relation to COVID-19 progression and death. The indices were tested by analysis of variance, receiver operating characteristic curve analysis, and binomial logistic regressions., Results: Patients with severe COVID-19 had significantly higher counts of neutrophils, eosinophils, and large immature cells (LIC), while decreased counts of platelets and monocytes. Lymphopenia was found in all of the patients, but without significant association with the outcomes. Patients with a LIC count ≥0.265 x 0 9 /L had 54.7% more odds of having COVID-19 progression. In multivariable analyses, platelets/neutrophil-to-lymphocyte ratio (P/NLR) and platelets-to-neutrophil radio (P/N) were significant independent predictors of COVID-19 progression and mortality. The odds of a poor outcome were two times higher in cases with P/NLR < 43 x 10 9 /L and P/N < 29 x 10 9 /L., Conclusion: Indices that include platelet count in combination with neutrophil and/or lymphocyte counts displayed the best discriminatory ability and prognostic value of COVID-19 outcomes. Additionally, LIC showed promising results in the early identification of severe COVID-19., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Objectives: While ovarian cancer is the third most common Lynch syndrome-associated cancer in women, there is no established screening strategy to identify Lynch syndrome in this population. The objective of this study was to assess whether the 4-item brief Family History Questionnaire can be used as a screening tool to identify women with ovarian cancer at risk of Lynch syndrome., Methods: In this prospective cohort study, participants with newly diagnosed non-serous, non-mucinous ovarian cancer completed the brief Family History Questionnaire, extended Family History Questionnaire, and had tumors assessed with immunohistochemistry for mismatch repair proteins, MLH1 methylation, and microsatellite instability testing. All underwent universal germline testing for Lynch syndrome. Performance characteristics were compared between the brief Family History Questionnaire, extended Family History Questionnaire, immunohistochemistry± MLH1 methylation, and microsatellite instability testing., Results: Of 215 participants, 169 (79%) were evaluable with both the brief Family History Questionnaire and germline mutation status; 12 of these 169 were confirmed to have Lynch syndrome (7%). 10 of 12 patients (83%) with Lynch syndrome were correctly identified by the brief Family History Questionnaire, compared with 6 of 11 (55%) by the extended Family History Questionnaire, 11 of 13 (85%) by immunohistochemistry± MLH1 methylation, and 9 of 11 (82%) by microsatellite instability testing. The sensitivity, specificity, positive predictive values, and negative predictive values of the brief Family History Questionnaire were 83%, 65%, 15%, and 98%, respectively. A combined approach with immunohistochemistry and the brief Family History Questionnaire correctly identified all 12 patients with Lynch syndrome. The brief Family History Questionnaire was more sensitive than the extended Family History Questionnaire and took <10 min for each patient to complete., Conclusions: The brief Family History Questionnaire alone or combined with immunohistochemistry may serve as an adequate screening strategy, especially in centers without access to universal tumor testing., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives : For stage IIIb-IV ovarian cancer, bevacizumab-containing treatment is considered the standard of care. The purpose of this study was to evaluate the efficacy of bevacizumab in combination with carboplatin and paclitaxel as a first-line treatment for advanced ovarian cancer. Materials and Methods : Eligible patients had stage IIIc-IV ovarian cancer according to the International Federation of Gynecology and Obstetrics with no clinical signs or symptoms of gastrointestinal obstruction or a history of abdominal fistulae, gastrointestinal perforation, or intra-abdominal abscess or evidence of rectosigmoid involvement by pelvic examination, bowel involvement on computed tomography, or clinical symptoms of bowel obstruction in the previous 6 months. After debulking surgery, the patients received 175 mg/m 2 paclitaxel and carboplatin (AUC 6) for the first six cycles and 7.5 mg/kg bevacizumab every three weeks up to 17 cycles until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was progression-free survival. The secondary endpoint was overall survival. Results : Between April 2017 and March 2020, 35 patients began study treatment. Bevacizumab was administered at 7.5 mg/kg in all the patients and for more than 7.5 months in 70% of them. The median progression-free survival was 20 months (95% CI: 16-23). The median overall survival was not reached. Conclusions : This was, to our knowledge, the first trial in Serbia to show progression-free survival and overall survival of combination regimens in advanced ovarian cancer. Based on the observed progression-free survival, bevacizumab combined with chemotherapy should be considered as a standard option in advanced ovarian cancer.

This study aimed to investigate the short-term effects of three magnesium (Mg) dietary supplements containing mineral immediately available for absorption on Mg biochemical status indices (ionized and total Mg), as well as their effects on electrolytes levels in healthy female young adults (n = 61). After a 10-days intervention period supplementation with powder/granulate containing Mg oxide led to an increase in both ionized Mg concentration and % in total Mg in comparison with the baseline. Supplementation with Mg citrate was associated with the significant increase in % of ionized fraction and decrease in serum total Mg concentration. By contrast, among participants consuming Mg carbonate in the form of effervescent tablets ionized Mg concentration and % in total Mg decreased, without detectable changes in serum total Mg. In conclusion, after the short-term supplementation period, Mg oxide demonstrated superior bioavailability compared to the other examined Mg supplements without affecting other minerals' levels., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Stress related to salmon aquaculture practices (handling, sub-optimal nutrition, diseases, and environmental problems) may compromise fish welfare. This study describes the effects of two hydrolyzed Debaryomyces hansenii yeast-based products (LAN4 and LAN6) on physiological and immune responses of Atlantic salmon ( Salmo salar ) parr exposed to short hypoxia stress. A commercial-like diet (control diet: CD) and two experimental diets (CD supplemented with 0.1% of either component LAN4 or LAN6) were fed to fish for 8 weeks. At the end of the feeding experiment, fish were exposed to 1-min hypoxia and samples were collected at 0, 1, 3, 6, 12, and 24 h post-stress. Results showed that plasma cortisol reached a peak at 1 h post-stress in CD and LAN6 groups, whereas no significant increase in cortisol levels was detected in the LAN4 group. Moreover, the LAN6 group enhanced IL-10 responses to hypoxia, when compared to the control and LAN4 group. This suggests a regulation of immunosuppressive profiles in fish fed LAN4. Hypoxia stress increased TNFα in all groups, which indicates that fish may compensate for the short-term stress response, by modulating innate immune molecules. The apparent suppression of hypoxia responses in the LAN4 group coincided with the detection of differences in goblet cells size and Muc-like proteins production in DI; and upregulation (1 h post-stress) of pathways related to oxygen transport, hemoglobin complex, and glutathione transferase activity and the downregulation of fatty acid metabolism (6 h post-stress) in gills. To conclude, a 1-min hypoxia stress exposure affects the response to stress and immunity; and D. hansenii -based yeast products are promising components in functional aquafeeds for salmon due to their ability to counteract possible consequences of hypoxic stress., Competing Interests: MC was employee in Lallemand SAS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Morales-Lange, Djordjevic, Gaudhaman, Press, Olson, Mydland, Mercado, Imarai, Castex and Øverland.)

In adult organisms, deregulation of the sonic hedgehog (SHH) signaling pathway is significantly correlated with different malignancies. Currently, data associating genetic polymorphisms in the SHH pathway with melanoma are scarce and largely unknown. The objective of our study was to elucidate an association between gene polymorphisms in the SHH pathway and prognosis of melanoma skin cancer patients. The current study investigated the association of PTCH1 (rs357564), SMO (rs2228617) and GLI1 (rs2228224, rs2228226), polymorphisms with melanoma predisposition and prognosis. Single-nucleotide polymorphisms were assessed by TaqMan SNP Genotyping Assays. The study involved 93 melanoma patients and 97 individuals in the control group. Melanoma patients with the variant mutant genotype GG of GLI1 rs2228226 polymorphism had poorer overall survival and recurrence-free survival (P = 0.0001 and P = 0.037, respectively). The multivariate analysis revealed that disease progression [hazard ratio (HR) = 14.434, P = 0.0001] and the GLI1 rs2228226 polymorphism (HR = 4.161, P = 0.006) persisted as independent prognostic factors. Mutated allele carriers (combined heterozygous and mutated genotypes) for GLI1 rs2228224 G and GLI1 rs2228226 G allele significantly increased melanoma risk [odds ratio (OR) = 2.261, P = 0.007; OR = 2.176, P = 0.010]. Our study demonstrated that genetic variants in GLI1, downstream member of the HH signaling pathway, are the risk factors for melanoma susceptibility and it can be a novel marker for melanoma prognosis. As a crucial SHH signaling member, GLI1 can also be regarded as a novel drug target for anti-cancer treatment in melanoma., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Context.—: Competency-based medical education relies on frequent formative in-service assessments to ascertain trainee progression. Currently at our institution, trainees receive a summative end-of-rotation In-Training Evaluation Report based on feedback collected from staff pathologists. There is no method of simulating report sign-out., Objective.—: To develop a formative in-service assessment tool that is able to simulate report sign-out and provide case-by-case feedback to trainees. Further, to compare time- versus competency-based assessment models., Design.—: Twenty-one pathology trainees were assessed for 20 months. Hot Seat Diagnosis by trainees and trainee assessment by pathologists were recorded in the laboratory information system. In the first iteration, trainees were assessed by using a time-based assessment scale on their ability to diagnose, report, use ancillary tests, comment on clinical implications, and provide intraoperative consultation and/or gross cases. The second iteration used a competency-based assessment scale. Trainees and pathologists completed surveys on the effectiveness of the In-Training Evaluation Report versus the Hot Seat Diagnosis tool., Results.—: Scores from both iterations correlated significantly with other assessment tools including the Resident In-Service Examination (r = 0.93, P = .04 and r = 0.87, P = .03). The competency-based model was better able to demonstrate improvement over time and stratify junior versus senior trainees than the time-based model. Trainees and pathologists rated Hot Seat Diagnosis as significantly more objective, detailed, and timely than the In-Training Evaluation Report, and effective at simulating report sign-out., Conclusions.—: Hot Seat Diagnosis is an effective tool for the formative in-service assessment of pathology trainees and simulation of report sign-out, with the competency-based model outperforming the time-based model.

Competing Interests: Declaration of interests KJJ reports speaker, advisory board, or consultant roles for Amgen, AstraZeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Novartis, and Purdue Pharma, and research funding from Eli Lilly and AstraZeneca. The other authors declare no competing interests.