Search

Introduction: Azoospermia affects more than 10% - 15% of infertile male subjects attending infertilty clinics. At present, testicular biopsy is the golden standard procedure for evaluating spermatogenesis status in men with azoospermia . Semen collection and analysis is a non-invasive method and has proven to be valuable in the evaluation of spermatogenesis. Identification of seminal plasma markers with testicular or extra-testicular origins have a great value in predicting the prescence of sperm in testicular tissue and presumptive cause of azoospermia. The aim of this study was to find such markers by comparing the content of seminal plasma using different methods in normospermic and azoospermic men.Matherials and Methods: Semen samples were collected from 200 men attending Avicenna Infertility Clinic (AIC) in Tehran, Iran. Semen samples were analysed according to WHO guidlines. The subjects were divided into two groups: normospermic (n = 100; group one) and azoospermic men (n = 100; group two) according to semen analysis results. Seminal plasma was separated by high speed centrifuagation and stored in -20 degrees C. Four markers including fructose, neutral alpha glucosidase (NalphaG), inhibin B and anti-Müllerian hormone (AMH) were measured in seminal plasma. Fructose and NalphaG were evaluated by spectrophotometry, while inhibin B and AMH were assessed by ELISA method. The spermatogenesis status in the azoospermic group was evaluated by histopathological method following testicular biopsy.Results: Fructose concentration showed no difference between the two groups. However, it was significantly correlated with sperm count (p < 0.01, r = -0.408). Seminal plasma inhibin B (OR: 1.01; 95%: CI: 1.005 - 1.016), AMH (OR: 1.63; 95% CI: 1.17 - 2.28) and NalphaG, (OR: 1.07; 95% CI: 1.04 - 1.1) levels were higher in normospermic subjects compared to azoospermic men. There were significant differences in inhibin B and AMH concentrations between the two groups based on the presence or absence of mature sperm in testicular biopsies (p < 0.01). Inhibin B concentration was positively correlated with sperm count in the normospermic group, however, NalphaG concentration correlated with sperm count of normospermic men (p < 0.01, r = 0.345) and the subjects'age in both groups.Conclusion: Inhibin B and AMH were correlated with the presence of sperm in testicular tissue samples. According to non-specific changes in inhibin B and AMH concentrations, identification of more specific molecular markers in seminal plasma to definitely evaluate the status of spermatogenesis is recommended. [ABSTRACT FROM AUTHOR]

The eukaryotic complexity involves the expression and regulation of genes via RNA-DNA, RNA-RNA, DNA-protein and RNA-protein interactions. Recently, the role of RNA molecules in the regulation of genes in higher organisms has become more evident, especially with the discovery that about 97% of the transcriptional output in higher organisms are represented as noncoding RNAs: rRNA, snoRNAs, tRNA, transposable elements, 5′ and 3′ untranslated regions, introns, intergenic regions and microRNAs. MicroRNAs function by negatively regulating gene expression via degradation or translational inhibition of their target mRNAs and thus participate in a wide variety of physiological and pathological cellular processes including: development, cell proliferation, differentiation, and apoptosis pathways. MicroRNA expression profiles in many types of cancers have been identified. Recent reports have revealed that the expression profiles of microRNAs change in various human cancers and appear to function as oncogenes or tumor suppressors. Abnormal microRNA expression has increasingly become a common feature of human cancers. In this review, we summarize the latest progress on the involvement of microRNAs in different types of cancer and their potential use as potential diagnostic and prognostic tumor biomarkers in the future. [ABSTRACT FROM AUTHOR]

Cancer incidence is projected to increase in the future and an effectual preventive strategy is required to face this challenge. Alteration of dietary habits is potentially an effective approach for reducing cancer risk. Assessment of biological effects of a specific food or bioactive component that is linked to cancer and prediction of individual susceptibility as a function of nutrientnutrient interactions and genetics is an essential element to evaluate the beneficiaries of dietary interventions. In general, the use of biomarkers to evaluate individuals susceptibilities to cancer must be easily accessible and reliable. However, the response of individuals to bioactive food components depends not only on the effective concentration of the bioactive food components, but also on the target tissues. This fact makes the response of individuals to food components vary from one individual to another. Nutrigenomics focuses on the understanding of interactions between genes and diet in an individual and how the response to bioactive food components is influenced by an individual's genes. Nutrients have shown to affect gene expression and to induce changes in DNA and protein molecules. Nutrigenomic approaches provide an opportunity to study how gene expression is regulated by nutrients and how nutrition affects gene variations and epigenetic events. Finding the components involved in interactions between genes and diet in an individual can potentially help identify target molecules important in preventing and/or reducing the symptoms of cancer. [ABSTRACT FROM AUTHOR]

In many acute leukemias, normal differentiation does not occur. However, in many cell lines derived from hematologic malignancies, differentiation or programmed cell death (apoptosis) can be induced by variety of agents including: Vitamin analogs, demethylating agents, cyclic AMP analogs and anti-proliferative agents. To the best of our knowledge there has been not any study specifically to analyze apoptotic and anti-proliferative effects of 4- HPR (a vitamin analog) in NB-4 cell line. To test whether this drug has activity in acute myeloid leukemia (AML), we first analyzed the antiproliferative effect of 4-HPR in one AML cell line (NB-4) using MTT Assay. Next we tested whether this drug induced apoptotic cell death. The ability of this compound to induce apoptosis of cancer cells was examined by Annexin V-FITC Assay using Flow cytometry. We also analyzed the cell cycle progression by PI staining using flow cytometry. Using MTT assay, NB-4 cells exhibited increased inhibition of proliferation at micromolar concentrations of 4-HPR at 24, 48 and 72 hrs post treatment. Flow cytometry analysis indicates that 4-HPR is a potent inducer of in vitro apoptotic cell death, and cell cycle analysis revealed an increase in S phase population. In total, the results indicate that 4-HPR is a strong inhibitor of AML cell proliferation and a potent inducer of in vitro apoptotic cell death. Further studies are required to evaluate the in vitro effects of 4-HPR in AML blasts derived from AML patients. [ABSTRACT FROM AUTHOR]

Introduction: In mammalian system, spermatozoa are not able to fertilize the oocyte immediately upon ejaculation, thus they undergo a series of biochemical and molecular changes which is termed capacitation. During sperm capacitation, signal transduction pathways are activated which lead to protein tyrosine phosphorylation. Tyrosine phosphorylated proteins have an important role in sperm capacitation such as hyperactive motility, interaction with zona pellucida and acrosome reaction. Evaluation of tyrosine phosphorylation pattern is important for further understanding of molecular mechanisms of fertilization and the etiology of sperm dysfunctions and abnormalities such as teratospermia. The goal of this study is to characterize tyrosine phosphorylation pattern in sperm proteins isolated from normospermic and teratospermic infertile men attending Avicenna Infertility Clinic in Tehran.Materials and Methods: Semen samples were collected and the spermatozoa were isolated using Percoll gradient centrifugation. Then the spermatozoa were incubated up to 6h at 37°C with 5% CO2 in 3% Bovine Serum Albumin-supplemented Ham's F-10 for capacitation to take place. The total proteins from spermatozoa were extracted and were subjected to SDS-PAGE before and after capacitation. To evaluate protein tyrosine phosphorylation pattern, western blotting with specific antibody against phosphorylated tyrosines was performed.Results: The results upon western blotting showed: 1) at least six protein bands were detected before capacitation in the spermatozoa from normospermic samples. However, comparable levels of tyrosine phosphorylation was not observed in the spermatozoa from teratospermic samples. 2) The intensity of protein tyrosine phosphorylation appears to have been increased during capacitation in the normospermic relative to the teratospermic group. Conclusion: For the first time, these findings demonstrate and suggest that the differences in the types of proteins and diminished tyrosine phosphorylation efficiency in sperm from teratospermic men may be responsible for their compromised capacitation and low fertilization success rates. [ABSTRACT FROM AUTHOR]

The subcutaneous injection is the most common method of administration of monoclonal antibodies (mAbs) due to the patient's comfort and cost-effectiveness. However, the available knowledge about the transport and absorption of this type of biotherapeutics after subcutaneous injection is limited. Here, a mathematical framework to study the subcutaneous drug delivery of mAbs from injection to lymphatic uptake is presented. A poro-hyperelastic model of the tissue is exploited to find the biomechanical response of the tissue together with a transport model based on an advection-diffusion equation in large-deformation poro-hyperelastic Media. The process of mAbs transport to the lymphatic system has two major parts. First is the initial phase, where mAbs are dispersed in the tissue due to momentum exerted by injection. This stage lasts for only a few minutes after the injection. Then there is the second stage, which can take tens of hours, and as a result, mAb molecules are transported from the subcutaneous layer towards initial lymphatics in the dermis to enter the lymphatic system. In this study, we investigate both stages. The process of plume formation, interstitial pressure, and velocity development is explored. Then, the effect of the injection delivery parameters, injection site, and sensitivity of long-term lymphatic uptake due to variability in permeability, diffusivity, viscosity, and binding of mAbs are investigated. Finally, we study two different injection scenarios with variable injection volume and drug concentration inside the syringe and evaluate them based on the rate of lymphatic uptake. We use our results to find an equivalent lymphatic uptake coefficient similar to the coefficient widely used in pharmacokinetic (PK) models to study the absorption of mAbs. Ultimately, we validate our computational model against available experiments in the literature., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was sponsored by Eli Lilly and Company. E.R. is a post-doctoral research associate, C.L. is a PhD student and A.M.A. is a professor in Mechanical Engineering at Purdue University. X.Z is former PhD student in Mechanical Engineering at Purdue University and currently a postdoctoral scholar in Department of radiation physics at Stanford University. G.H.S is a vice president at Eli Lilly and company., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Deformability is one of the critical attributes of nanoparticle (NP) drug carriers, along with size, shape, and surface properties. It affects various aspects of NP biotransport, ranging from circulation and biodistribution to interactions with biological barriers and target cells. Recent studies report additional roles of NP deformability in biotransport processes, including protein corona formation, intracellular trafficking, and organelle distribution. This review focuses on the literature published in the past five years to update our understanding of NP deformability and its effect on NP biotransport. We introduce different methods of modulating and evaluating NP deformability and showcase recent studies that compare a series of NPs in their performance in biotransport events at all levels, highlighting the consensus and disagreement of the findings. It concludes with a perspective on the intricacy of systematic investigation of NP deformability and future opportunities to advance its control toward optimal drug delivery., Competing Interests: Declaration of competing interest 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., (Copyright © 2024. Published by Elsevier B.V.)

Understanding the rheology of minipig and human skin is crucial for enhancing drug delivery methods, particularly for injections. Despite many studies on skin's viscoelasticity, especially the subcutaneous layer, comparative analyses across different clinical sites are scarce, as is data on the impact of hydration or lipid levels. This study employs shear rheology and lipid analysis to evaluate viscoelasticity and lipid content across three anatomical locations-breast, belly, and neck and three different depth layers in Yucatan minipigs. It reports on how viscoelastic properties change with frequency, time, and strain, noting strain-stiffening and shear-thinning at high strain amplitudes. Human male and female abdominal tissues are also compared to minipig tissues, highlighting distinct viscoelastic traits and lipid's role in them. The findings suggest the existence of species, anatomical location, tissue depth, and sex-based rheological differences. Furthermore, the use of male minipig models for studying human male subcutaneous tissue is discussed., (© 2024. The Author(s) under exclusive licence to Biomedical Engineering Society.)

This paper studies the transport of monoclonal antibodies through skin tissue and initial lymphatics, which impacts the pharmacokinetics of monoclonal antibodies. Our model integrates a macroscale representation of the entire skin tissue with a mesoscale model that focuses on the papillary dermis layer. Our results indicate that it takes hours for the drugs to disperse from the injection site to the papillary dermis before entering the initial lymphatics. Additionally, we observe an inhomogeneous drug distribution in the interstitial space of the papillary dermis, with higher drug concentrations near initial lymphatics and lower concentrations near blood capillaries. To validate our model, we compare our numerical simulation results with experimental data, finding a good alignment. Our parametric studies on the drug molecule properties and injection parameters suggest that a higher diffusion coefficient increases the transport and uptake rate while binding slows down these processes. Furthermore, shallower injection depths lead to faster lymphatic uptake, whereas the size of the injection plume has a minor effect on the uptake rate. These findings advance our understanding of drug transport and lymphatic absorption after subcutaneous injection, offering valuable insights for optimizing drug delivery strategies and the design of biotherapeutics., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Subcutaneous (SC) injection of protein-based therapeutics is a convenient and clinically established drug delivery method. However, progress is needed to increase the bioavailability. Transport of low molecular weight ( M w ) biotherapeutics such as insulin and small molecule contrast agents such as lipiodol has been studied using X-ray computed tomography (CT). This analysis, however, does not translate to the investigation of higher M w therapeutics, such as monoclonal antibodies (mAbs), due to differences in molecular and formulation properties. In this study, an iodinated fluorescein analog rose bengal (RB) was used as a radiopaque and fluorescent label to track the distribution of bovine serum albumin (BSA) compared against unconjugated RB and sodium iodide (NaI) via CT and confocal microscopy following injection into ex vivo porcine SC tissue. Importantly, the high concentration BSA-RB exhibited viscosities more like that of viscous biologics than the small molecule contrast agents, suggesting that the labeled protein may serve as a more suitable formulation for the investigation of injection plumes. Three-dimensional (3D) renderings of the injection plumes showed that the BSA-RB distribution was markedly different from unconjugated RB and NaI, indicating the need for direct visualization of large protein therapeutics using conjugated tags rather than using small molecule tracers. Whereas this proof-of-concept study shows the novel use of RB as a label for tracking BSA distribution, our experimental approach may be applied to high M w biologics, including mAbs. These studies could provide crucial information about diffusion in SC tissue and the influence of injection parameters on distribution, transport, and downstream bioavailability.

The development, storage, transport, and subcutaneous delivery of highly concentrated monoclonal antibody formulations pose significant challenges due to the high solution viscosity and low diffusion of the antibody molecules in crowded environments. These issues often stem from the self-associating behavior of the antibody molecules, potentially leading to aggregation. In this work, we used a dissipative particle dynamics-based coarse-grained model to investigate the diffusion behavior of IgG1 antibody molecules in aqueous solutions with 15 and 32 mM NaCl and antibody concentrations ranging from 10 to 400 mg/mL. We determined the coarse-grained interaction parameters by matching the calculated structure factor with the computational and experimental data from the literature. Our results indicate Fickian diffusion for antibody concentrations of 10 and 25 mg/mL and anomalous diffusion for concentrations exceeding 50 mg/mL. The anomalous diffusion was observed for ∼0.33 to 0.4 μs, followed by Fickian diffusion for all antibody concentrations. We observed a strong linear correlation between the diffusion behavior of the antibody molecules (diffusion coefficient D and anomalous diffusion exponent α) and the amount of aggregates present in the solution and between the amount of aggregates and the Coulomb interaction energy. The investigation of underlying mechanisms for anomalous diffusion revealed that in crowded environments at high antibody concentrations, the attractive interaction between electrostatically complementary regions of the antibody molecules could further bring the neighboring molecules closer to one another, ultimately resulting in aggregate formation. Further, the Coulomb attraction can continue to draw more molecules together, forming larger aggregates.

Despite the growing popularity of subcutaneous (SC) administration for monoclonal antibodies (mAbs), there remains a limited understanding of the significance of mAb transport rate constants within the interstitial space and the lymphatic system on their pharmacokinetics. To bridge this knowledge gap, we introduce a compartmental model for subcutaneously administered mAbs. Our model differentiates FcRn-expressing cells across various sites, and the model predictions agree with experimental data from both human and rat studies. Our findings indicate that the time to reach the maximum mAb concentration in the plasma, denoted by T max , displays a weak positive correlation with mAb half-life and a negligible correlation with bioavailability. In contrast, the half-life of mAbs exhibits a strong positive correlation with bioavailability. Moreover, the rate of mAb transport from lymph to plasma significantly affects the mAb half-life. Increasing the transport rates of mAbs from the injection site to the lymph or from lymph to plasma enhances bioavailability. These insights, combined with our compartmental model, contribute to a deeper understanding of the pharmacokinetics of subcutaneously administered mAbs., Competing Interests: Declaration of competing interest XZ and YL are research assistants, AMA is a professor in Mechanical Engineering at Purdue University., (Copyright © 2023 Elsevier B.V. All rights reserved.)

While significant progress has been made in the modeling and simulation of uniform fiber suspensions, no existing model has been validated for industrially-relevant concentrated suspensions containing fibers of multiple aspect ratios. In the present work, we investigate bi-disperse suspensions with two fiber populations in varying aspect ratios in a steady shear flow using direct numerical simulations. Moreover, we measure the suspension viscosity by creating a controlled length bidispersity for nylon fibers suspended in a Newtonian fluid. The results showed good agreement between the experimentally measured and numerically predicted viscosity for bi-disperse suspensions. The ratio between the aspect ratio of large to small fibers (size ratio) and the volume fraction of large fibers (composition) in bi-disperse systems strongly affected the rheological behavior of the suspension. The increment of relative viscosity associated with size ratio and composition can be explained by the decrease in the maximum flowable limit or jamming volume fraction. Moreover, the relative viscosity of bi-disperse suspensions collapses, when plotted against the reduced volume fraction, demonstrating the controlling influence of the jamming fraction in bi-disperse fiber suspensions.

Subcutaneous injection of monoclonal antibodies (mAbs) has experienced unprecedented growth in the pharmaceutical industry due to its benefits in patient compliance and cost-effectiveness. However, the impact of different injection techniques and autoinjector devices on the drug's transport and uptake is poorly understood. Here, we develop a biphasic large-deformation chemomechanical model that accounts for the components of the extracellular matrix that govern solid deformation and fluid flow within the subcutaneous tissue: interstitial fluid, collagen fibers and negatively charged proteoglycan aggregates. We use this model to build a high-fidelity representation of a virtual patient performing a subcutaneous injection of mAbs. We analyze the impact of the pinch and stretch methods on the injection dynamics and the use of different handheld autoinjector devices. The results suggest that autoinjector base plates with a larger device-skin contact area cause significantly lower tissue mechanical stress, fluid pressure and fluid velocity during the injection process. Our simulations indicate that the stretch technique presents a higher risk of intramuscular injection for autoinjectors with a relatively long needle insertion depth., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Implantable, bioresorbable drug delivery systems offer an alternative to current drug administration techniques; allowing for patient-tailored drug dosage, while also increasing patient compliance. Mechanistic mathematical modeling allows for the acceleration of the design of the release systems, and for prediction of physical anomalies that are not intuitive and may otherwise elude discovery. This study investigates short-term drug release as a function of water-mediated polymer phase inversion into a solid depot within hours to days, as well as long-term hydrolysis-mediated degradation and erosion of the implant over the next few weeks. Finite difference methods are used to model spatial and temporal changes in polymer phase inversion, solidification, and hydrolysis. Modeling reveals the impact of non-uniform drug distribution, production and transport of H + ions, and localized polymer degradation on the diffusion of water, drug, and hydrolyzed polymer byproducts. Compared to experimental data, the computational model accurately predicts the drug release during the solidification of implants over days and drug release profiles over weeks from microspheres and implants. This work offers new insight into the impact of various parameters on drug release profiles, and is a new tool to accelerate the design process for release systems to meet a patient specific clinical need., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Lymphatic uptake is essential for transporting nutrients, wastes, immune cells, and therapeutic proteins. Despite its importance, the literature lacks a quantitative analysis of the factors that affect lymphatic uptake, including interstitial pressure, downstream pressure, and tissue deformation. In this paper, we present a coupled model of a poroelastic tissue with initial lymphatics and quantify the impact of these factors on the rate of lymphatic uptake. Our results indicate that the lymphatic uptake increases with the amplitude of the oscillating downstream pressure when the amplitude exceeds a threshold. Additionally, the cross-sectional area of initial lymphatics increases with the volumetric strain of the tissue, while the interstitial pressure increases when the strain rate becomes negative. Therefore, the lymphatic uptake reaches its maximum when the tissue has positive volumetric strain while being compressed. We have also investigated the effect of intersection angles and positions of two initial lymphatics and concluded that they have minor impacts on lymphatic uptake. However, the lymphatic uptake per unit length of initial lymphatics decreases with their total length. These findings advance our understanding of lymphatic uptake and can guide the development of strategies to accelerate the transport of therapeutics., Competing Interests: Declaration of competing interest None Declared. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the research reported in this work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The predisposition of humans to metabolic syndrome is affected by many factors, including diet and lifestyle. Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are a set of carbohydrates that are fermented by gut microbiota. In animal studies, supplementation with FODMAP-rich diets as prebiotics can alter body composition and gut microbiota. This study evaluates any relationship between FODMAP and metabolic syndrome risk factors among adults with metabolic syndrome in Iran., Methods: This cross-sectional study is based on sociodemographic information from 347 overweight and obese participants selected from outpatient clinics through public declaration. Participants body composition and anthropometric measures were also determined. A validated Food Frequency Questionnaire (FFQ) with 168 questions was used to collect dietary data. Biochemical parameters, including serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), fasting serum glucose (FSG), and insulin levels, were determined by enzymatic methods. In addition, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated., Results: In moderate FODMAP and low FODMAP groups, lower waist-to-hip ratio (WHR) and higher fat-free mass (FFM) were achieved in higher tertiles. In high FODMAP groups, higher systolic blood pressure (SBP) was shown in the higher tertile (P < 0.05). Higher insulin, HOMA-IR, and lower QUICKI in the second tertile of the high FODMAP group were also observed., Conclusion: Findings of this study highlight the potential role of FODMAP in managing metabolic syndrome and open a new field of research., (© 2023. BioMed Central Ltd., part of Springer Nature.)

In this work, we study the role of viscoelastic instability in the mechanical dispersion of fluid flow through porous media at high Péclet numbers. Using microfluidic experiments and numerical simulations, we show that viscoelastic instability in flow through a hexagonally ordered (staggered) medium strongly enhances dispersion transverse to the mean flow direction with increasing Weissenberg number (Wi). In contrast, preferential flow paths can quench the elastic instability in disordered media, which has two important consequences for transport: first, the lack of chaotic velocity fluctuations reduces transverse dispersion relative to unstable flows. Second, the amplification of flow along preferential paths with increasing Wi causes strongly-correlated stream-wise flow that enhances longitudinal dispersion. Finally, we illustrate how the observed dispersion phenomena can be understood through the lens of Lagrangian stretching manifolds, which act as advective transport barriers and coincide with high stress regions in these viscoelastic porous media flows.

Background: Metabolic syndrome (MetS) is presented with a cluster of cardio-metabolic risk factors with widespread prevalence. In the present case-control study, we aimed to examine the relationship between several minerals and renal function tests with the components of MetS in individuals with obesity., Methods: This study included 127 individuals with obesity of both gender with or without MetS as the case and control, respectively. MetS was characterized based on the Adult Treatment Panel III (ATP III) criteria. Anthropometric variables and blood pressure were recorded. Mineral status including serum magnesium, copper, calcium, phosphorous, and iron were measured using standard colorimetric methods. Also, the serum lipid levels, concentrations of oxidized low-density lipoprotein (Ox-LDL), and renal function tests, including total protein, albumin, urea, creatinine, and uric acid were evaluated using commercial enzyme-linked immunosorbent assay (ELISA) kits., Results: According to our results, individuals with obesity and MetS had higher levels of waist circumference (WC) and diastolic blood pressure (P < 0.05) compared to individuals with obesity and without MetS. Moreover, individuals with obesity and MetS had higher levels of serum total cholesterol (TC), triglyceride (TG), insulin, and iron (P < 0.05). In individuals with obesity and MetS, iron and albumin showed a positive relationship with LDL cholesterol and TG concentrations, respectively (P < 0.05 for all of them). Also, there was a positive association between serum magnesium and Ox- LDL in individuals with obesity with MetS. While, in individuals with obesity and without MetS, only a positive association between urea and uric acid with WC was observed (P < 0.05)., Conclusion: Our results suggest that disturbed serum lipids in obesity-metabolic syndrome is associated with homeostatic changes in the level of minerals or proteins that are involved in their metabolism. Although, further studies are needed to better explain and clarify the underlying mechanism of observed relationships., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Metabolic syndrome (MetS), as a cluster of cardiometabolic risk factors, is a global public health concern due to its increasing prevalence. Considering the previous evidence of the association between carbohydrate quality and cardiometabolic risk factors, our study was aimed to evaluate any possible association between carbohydrate quality index (CQI) and cardiometabolic risk factors among obese adults., Methods: In this cross-sectional study, 336 apparently healthy individuals with obesity were participated. Dietary intake was assessed by a semi-quantitative Food Frequency Questionnaire (FFQ), including 168 food items validated for the Iranian population. CQI was calculated with three components of solid carbohydrates to total carbohydrates ratio, dietary fiber intake, and dietary glycemic index (GI). Body composition was determined by bioelectrical impedance analysis (BIA). Blood pressure was measured by sphygmomanometer and enzymatic methods were used to evaluate serum lipid, glucose, and insulin concentrations., Results: Subjects in the third quartile of CQI had significantly lower systolic blood pressure (SBP) (P = 0.03) and diastolic blood pressure (DBP) (P = 0.01). Participants in the higher quartiles of CQI had more intake of energy, carbohydrates, fat, saturated fatty acid (SFA), and mono-saturated fatty acid (MUFA) (P < 0.05). Moreover, the homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in the second quartile of CQI [odds ratio (OR) = 0.146, P = 0.01) after adjustment for age, body mass index (BMI), sex, physical activity, socioeconomic status (SES) and energy intake., Conclusion: According to our findings, a higher quality of dietary carbohydrates, determined by CQI, could be associated with a lower risk of hypertension., (© 2023. The Author(s).)

Background: There is conflicting evidence on the relationship between dietary choline and betaine with metabolic markers and anthropometric characteristics. The aim of this study is to investigate the relationship between the interaction effects of dietary choline and betaine and physical activity (PA) on circulating creatine kinase (CK), metabolic and glycemic markers, and anthropometric characteristics in active youth., Methods: In this cross-sectional study, data were collected from 120 to 18 to 35-year-old people. The food frequency questionnaire was used to assess dietary data; United States Department of Agriculture website was used to calculate choline and betaine in foods. CK, fasting blood sugar (FBS) and lipid profile markers were measured with ELISA kits. Low-density lipoprotein, and insulin sensitivity markers were calculated. Sociodemographic status, physical activity, and anthropometric characteristics were assessed based on a valid and reliable method. Analysis of co-variance (ANCOVA) tests adjusted for sex, PA, age, energy, and body mass index were used., Results: Increasing dietary betaine and total choline and betaine was positively related to weight, waist-to-hip ratio, fat-free mass and bone mass (P < 0.05). Increasing dietary betaine lowered total cholesterol (P = 0.032) and increased high density lipoprotein (HDL) (P = 0.049). The interaction effect of dietary choline and physical activity improved insulin resistance (P < 0.05). As well as dietary betaine interacted with physical activity increased HDL (P = 0.049). In addition, dietary total choline and betaine interacted with physical activity decreased FBS (P = 0.047)., Conclusions: In general, increasing dietary choline and betaine along with moderate and high physical activity improved insulin resistance, increased HDL, and lowered FBS in the higher tertiles of dietary choline and betaine., (© 2023. The Author(s).)

Background: Oxidative stress (OS) is associated with a variety of non-communicable diseases, including MetS, diabetes mellitus, metabolic syndrome, and cardiovascular disease through increased production of reactive oxygen species (ROS) and impairment of antioxidant defense mechanisms. Antioxidants can protect cells against free radical damage, so it seems important to determine the relationship between the quality of dietary antioxidants intake and chronic diseases. The Dietary Antioxidant Quality Score (DAQS) is obtained by adding the daily intake of known dietary vitamins and minerals, including selenium, zinc, vitamin A, vitamin C, and vitamin E, compared to the recommended daily intake (RDI). Therefore, this study aims to determine the relationship between DAQS, serum lipids, markers of glucose homeostasis, blood pressure and anthropometric features among obese adults., Methods: In the present cross-sectional study, 338 individuals who were obese (BMI ≥ 30 kg/m 2 ) aged 20-50 years were recruited from Tabriz and Tehran, Iran. A validated semi-quantitative Food Frequency Questionnaire (FFQ) with 168 food items was used to quantify dietary consumption; accordingly, DAQS was computed. Blood biomarkers were measured using enzyme-linked immunosorbent assay (ELISA) kits. A standard mercury sphygmomanometer was used to assess blood pressure, and bioelectrical impedance analysis (BIA) was performed to determine body composition. The association between the DAQS tertiles and biochemical variables was investigated using multinomial logistic regression., Results: Participants in the highest tertile of DAQS have a lower diastolic blood pressure (DBP) values in all of the adjusted models [odds ratio (OR) = 0.920; confidence interval (CI)= 0.852-0.993, P-value = 0.03] in the analysis of co-variance (ANCOVA) model. Similarly, subjects at the second tertile of DAQS had lower DBP compared with the first tertile in age and sex-adjusted model [OR= 0.937; CI= 0.882-0.997]. There was no statistically significant difference for other metabolic parameters in different DAQS tertiles., Conclusion: According to our findings, higher DAQS was associated with lower DBP among obese adults with obesity in two major cities of Iran (Tehran and Tabriz). Other studies with interventional design are needed to better elucidate these associations and underlying mechanisms., (© 2023. The Author(s).)

Convective transport of drug solutes in biological tissues is regulated by the interstitial fluid pressure, which plays a crucial role in drug absorption into the lymphatic system through the subcutaneous (SC) injection. In this paper, an approximate continuum poroelasticity model is developed to simulate the pressure evolution in the soft porous tissue during an SC injection. This poroelastic model mimics the deformation of the tissue by introducing the time variation of the interstitial fluid pressure. The advantage of this method lies in its computational time efficiency and simplicity, and it can accurately model the relaxation of pressure. The interstitial fluid pressure obtained using the proposed model is validated against both the analytical and the numerical solution of the poroelastic tissue model. The decreasing elasticity elongates the relaxation time of pressure, and the sensitivity of pressure relaxation to elasticity decreases with the hydraulic permeability, while the increasing porosity and permeability due to deformation alleviate the high pressure. An improved Kedem-Katchalsky model is developed to study solute transport across the lymphatic vessel network, including convection and diffusion in the multi-layered poroelastic tissue with a hybrid discrete-continuum vessel network embedded inside. At last, the effect of different structures of the lymphatic vessel network, such as fractal trees and Voronoi structure, on the lymphatic uptake is investigated. In this paper, we provide a novel and time-efficient computational model for solute transport across the lymphatic vasculature connecting the microscopic properties of the lymphatic vessel membrane to the macroscopic drug absorption.

In recent years, significant progress has been made in the studies of the spring-driven autoinjector, leading to an improved understanding of this device and its interactions with tissue and therapeutic proteins. The development of simulation tools that have been validated against experiments has also enhanced the prediction of the performance of spring-driven autoinjectors. This paper aims to address critical hydrodynamic considerations that impact the design of spring-driven autoinjectors, with a specific emphasis on sloshing and cavitation. Additionally, we present a framework that integrates simulation tools to predict the performance of spring-driven autoinjectors and optimize their design. This work is valuable to the pharmaceutic industry, as it provides crucial insights into the development of spring-driven autoinjectors and therapeutic proteins. This work can also enhance the efficacy and safety of the delivery of therapeutic proteins, ultimately improving patient outcomes., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The hypothesis of the effect of the insulinogenic effects of diet on the development of cardiometabolic disorders has been suggested, but limited data are available for adults with obesity. This study aimed to determine the association of dietary insulin index (DII) and dietary insulin load (DIL) with cardiometabolic risk factors among Iranian adults with obesity., Methods: The study was conducted with a total of 347 adults aged 20-50 years in Tabriz, Iran. Usual dietary intake was assessed through a validated 147-item food frequency questionnaire (FFQ). DIL was computed using published food insulin index (FII) data. DII was calculated by dividing DIL by the total energy intake of each participant. Multinational logistic regression analysis was performed to evaluate the association between DII and DIL and cardiometabolic risk factors., Results: Mean age of participants was 40.78 ± 9.23 y, and mean body mass index (BMI) was 32.62 ± 4.80 kg/m2. Mean of DII and DIL was 73.15 ± 37.60 and 196,242 ± 100,181. Participants with higher DII had higher BMI, weight, waist circumference (WC), and blood concentrations of triglyceride (TG) and Homeostasis model assessment insulin resistance index (HOMA-IR) (P < 0.05). After taking potential confounders into account, DIL was positively associated with MetS (OR: 2.58; 95% CI: 1.03-6.46), and high blood pressure (OR: 1.61; 95% CI: 1.13-6.56). Moreover, after adjustment for potential confounders, moderate DII was associated with increased odds of MetS (OR: 1.54, 95% CI: 1.36-4.21), high TG (OR, 1.25; 95% CI, 1.17-5.02), and high blood pressure (OR: 1.88; 95% CI: 1.06-7.86)., Conclusion: This population-based study revealed that adults with higher DII and DIL associated with cardiometabolic risk factors and consequently, replacement of high with low DII and DIL may have reduce the risk of cardiometabolic disorders. Further studies with longitudinal design are required to confirm these findings., (© 2023. The Author(s).)

Background: Choline is an important metabolite involved in phospholipids synthesis, including serum lipids, and is the immediate precursor of betaine. There are numerous studies with inconsistent results that evaluated the association between dietary choline intakes with cardiovascular risk factors. In addition, the association between dietary betaine and choline intakes with cardio-metabolic risk factors is not well studied. In the current study, our aim was to evaluate dietary choline and betaine intakes in the usual diet of obese individuals and to assess its association with serum lipids, blood pressure and glycemic markers among obese individuals., Methods: We recruited a total number of 359 obese people aged between 20 and 50 years in the present study. A semi-quantitative food frequency questionnaire (FFQ) was used for dietary assessment; dietary choline and betaine intakes were calculated using the United States Department of Agriculture (USDA) database. National cholesterol education program adult treatment panel (NCEP-ATP)-III criteria was used metabolic syndrome (MetS) definition. Enzymatic methods were used to assess biochemical variables. Body composition was measured with the bioelectrical impedance analysis (BIA) method., Results: Higher body mass index (BMI), waist to hip ratio (WHR), fat-free mass (FFM) and basal metabolic rate (BMR) were observed in higher tertiles of dietary choline intake (P < 0.01). There was no significant difference in terms of biochemical parameters among different tertiles of dietary choline intake, while systolic blood pressure (SBP) and diastolic blood pressure (DBP) were reduced in higher betaine tertiles (P < 0.05). For total dietary choline and betaine intakes, there was a reduction in DBP and low density lipoprotein (LDL) concentrations (P < 0.05). Also, a non-significant reduction in serum total cholesterol (TC), triglyceride (TG) and MetS prevalence was observed in higher tertiles of dietary choline and betaine intakes. After classification of the study population according to MetS status, there was no significant difference in biochemical variables in subjects with MetS (P > 0.05), while in the non-MetS group, SBP, DBP, TG and insulin levels reduced in higher tertiles of dietary betaine and choline (P > 0.05)., Conclusion: According to our findings, higher dietary intakes of choline and betaine were associated with lower levels of blood pressure and LDL concentrations among obese individuals. Further studies are warranted to confirm the results of the current study., (© 2023. The Author(s).)

Cell tracking algorithms have been used to extract cell counts and motility information from time-lapse images of migrating cells. However, these algorithms often fail when the collected images have cells with spatially and temporally varying features, such as morphology, position, and signal-to-noise ratio. Consequently, state-of-the-art algorithms are not robust or reliable because they require manual inputs to overcome the cell feature changes. To address these issues, we present a fully automated, adaptive, and robust feature-based cell tracking algorithm for the accurate detection and tracking of cells in time-lapse images. Our algorithm tackles measurement limitations twofold. First, we use Hessian filtering and adaptive thresholding to detect the cells in images, overcoming spatial feature variations among the existing cells without manually changing the input thresholds. Second, cell feature parameters are measured, including position, diameter, mean intensity, area, and orientation, and these parameters are simultaneously used to accurately track the cells between subsequent frames, even under poor temporal resolution. Our technique achieved a minimum of 92% detection and tracking accuracy, compared to 16% from Mosaic and Trackmate. Our improved method allows for extended tracking and characterization of heterogeneous cell behavior that are of particular interest for intravital imaging users., (© 2022. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Background: Dietary indices and scores are valuable predictive markers against chronic diseases. Several previous studies have revealed the beneficial effects of diabetes risk reduction score (DRRS) against diabetes and cancer incidence. However, its association with metabolic abnormalities among obese individuals have not been revealed before. In the current study, we aimed to investigate the association between DRRS and metabolic risk factors among obese individuals., Methods: In the current cross-sectional study, 342 obese individuals [Body mass index (BMI) ≥ 30 kg/m 2 ] aged 20-50 years were included. Dietary intake was assessed by a validated semi-quantitative food frequency questionnaire (FFQ) of 168 food items and DRRS was calculated. Metabolic syndrome (MetS) was defined based on the guidelines of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III). Enzymatic methods were used to assess serum lipids, glucose, and insulin concentrations. Blood pressure was measured by a sphygmomanometer and body composition with bioelectrical impedance analysis (BIA)., Results: Those with a higher adherence to DRRS had a significantly higher intake of energy, fiber, and lower protein compared with those in the lower quartiles. Moreover, lower intakes of trans fats, meat, sugar sweetened beverages (SSB), and glycemic index (GI) with higher intakes of fruits, cereal fiber, polyunsaturated fatty acids/ saturated fatty acids (PUFA/ SFA) ratio, coffee, and nuts were observed in the highest versus lowest DRRS categories. Lower systolic blood pressure, diastolic blood pressure, triglyceride and, higher high-density lipoprotein values were observed in higher DRRS categories. Logistic regression analysis showed that hypertension was significantly associated with adherence to DRRS among obese individuals, the odds ratio (OR) was 0.686 (95% confidence interval [CI], 0.26-0.84) after adjustment for potential confounders. But the risk of other components of MetS was not significantly associated with higher quartiles of adherence to DRRS. Also, a non-significantly lower prevalence of MetS was observed in the higher quartile of DRRS., Conclusions: According to the results of the current study, higher DRRS was associated with lower blood pressure, modified serum lipids, and lower Mets prevalence. Further studies in different populations are warranted for better generalization of the obtained findings., (© 2023. The Author(s).)

Background: Several previous investigations have examined the brain-protective role of the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. However, more knowledge is needed about the MIND diet's other favorable impacts. The purpose of this study was to examine the relationship between the MIND diet, mental health, and metabolic markers in individuals with obesity., Methods: In this cross-sectional study, we included 339 individuals with obesity (BMI ≥ 30 kg/m 2 ) aged 20-50 years. We utilized a semi-quantitative Food Frequency Questionnaire (FFQ), we assessed dietary intake, including 168 food items, and calculated the value of MIND. Metabolic syndrome (MetS) was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines. We assessed biochemical parameters using Enzymatic methods. Blood pressure and body composition were also determined., Results: Higher tertiles of the MIND diet score were associated with significantly higher energy intake, macronutrients, and brain-healthy food intakes (P < 0.001). Among the brain-unhealthy foods, only the intake of sweets and pastries was significantly lower in the highest versus lowest MIND tertiles. We also observed lower odds of stress (P < 0.05) and higher insulin sensitivity (P < 0.05) in the highest versus lowest MIND diet tertiles. We witnessed no significant changes in other parameters., Conclusion: Lower stress levels and higher insulin sensitivity independent of some confounders like age, BMI, sex, and physical activity were associated with the highest tertile of MIND diet score., (© 2023. The Author(s).)

Concentrated suspensions of particles at volume fractions ( ϕ ) ≥ 0.5 often exhibit complex rheological behavior, transitioning from shear thinning to shear thickening as the shear stress or shear rate is increased. These suspensions can be extruded to form 3D structures, with non-adsorbing polymers often added as rheology modifiers to improve printability. Understanding how non-adsorbing polymers affect the suspension rheology, particularly the onset of shear thickening, is critical to the design of particle inks that will extrude uniformly. In this work, we examine the rheology of concentrated aqueous suspensions of colloidal alumina particles and the effects of adding non-adsorbing polyvinylpyrrolidone (PVP). First, we show that suspensions with ϕ alumina = 0.560-0.575 exhibited discontinuous shear thickening (DST), where the viscosity increased by up to two orders of magnitude above an onset stress ( τ min ). Increasing ϕ alumina from 0.550 to 0.575 increased the viscosity and yield stress in the shear thinning regime and decreased τ min . Next, PVP was added at concentrations within the dilute and semi-dilute non-entangled regimes of polymer conformation ( ϕ PVP = 0.005-0.050) to suspensions with constant ϕ alumina = 0.550. DST was observed in all cases and increasing ϕ PVP increased the viscosity and yield stress. Interestingly, increasing ϕ PVP also increased τ min . We posit that the free PVP chains act as lubricants between alumina particles, increasing the stress needed to induce thickening. Finally, we demonstrate through direct comparisons of suspensions with and without PVP how non-adsorbing polymer addition can extend the extrusion processing window due to the increase in τ min .

Subcutaneous administration is a common approach for the delivery of biotherapeutics, which is achieved mainly through the absorption across lymphatic vessels. In this paper, the drug transport and lymphatic uptake through a three-dimensional hybrid discrete-continuum vessel network in the skin tissue are investigated through high-fidelity numerical simulations. We find that the local lymphatic uptake through the explicit vessels significantly affects macroscopic drug absorption. The diffusion of drug solute through the explicit vessel network affects the lymphatic uptake after the injection. This effect, however, cannot be captured using previously developed continuum models. The lymphatic uptake is dominated by the convection due to lymphatic drainage driven by the pressure difference, which is rarely studied in experiments and simulations. Furthermore, the effects of injection volume and depth on the lymphatic uptake are investigated in a multi-layered domain. We find that the injection volume significantly affects the rate of lymphatic uptake through the heterogeneous vessel network, while the injection depth has little influence, which is consistent with the experimental results. At last, the binding and metabolism of drug molecules are studied to bridge the simulations to the drug clearance experients. We provide a new approach to study the diffusion and convection of drug molecules into the lymphatic system through the hybrid vessel network., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Therapeutic macromolecules possess properties such as size and electrostatic charge that will dictate their transport through subcutaneous (SC) tissue and ultimate bioavailability and efficacy. To improve therapeutic design, platforms that systematically measure the transport of macromolecules as a function of both drug and tissue properties are needed. We utilize a Transwell chamber with tunable collagen-hyaluronic acid (ColHA) hydrogels as an in vitro model to determine mass transport of macromolecules using non-invasive UV spectroscopy. Increasing hyaluronic acid (HA) concentration from 0 to 2 mg/mL within collagen gels decreases the mass transport of five macromolecules independent of size and charge and results in a maximum decrease in recovery of 23.3% in the case of bovine immunoglobulin G (IgG). However, in a pure 10 mg/mL HA solution, negatively-charged macromolecules bovine serum albumin (BSA), β-lactoglobulin (BLg), dextran (Dex), and IgG had drastically increased recovery by 20-40% compared to their performance in ColHA matrices. This result was different from the positively-charged macromolecule Lysozyme (Lys), which, despite its small size, showed reduced recovery by 3% in pure HA. These results demonstrate two distinct regimes of mass transport within our tissue model. In the presence of both collagen and HA, increasing HA concentrations decrease mass transport; however, in the absence of collagen, the high negative charge of HA sequesters and increases residence time of positively-charged macromolecules and decreases residence time of negatively-charged macromolecules. Through our approach, ColHA hydrogels serve as a platform for the systematic evaluation of therapeutic macromolecule transport as a function of molecular characteristics., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Subcutaneous injection of therapeutic monoclonal antibodies (mAbs) has become one of the fastest-growing fields in the pharmaceutical industry. The transport and mechanical processes behind large volume injections are poorly understood. Here, we leverage a large-deformation poroelastic model to study high-dose, high-speed subcutaneous injection. We account for the anisotropy of subcutaneous tissue using of a fibril-reinforced porohyperelastic model. We also incorporate the multi-layer structure of the skin tissue, generating data-driven geometrical models of the tissue layers using histological data. We analyze the impact of handheld autoinjectors on the injection dynamics for different patient forces. Our simulations show the importance of considering the large deformation approach to model large injection volumes. This work opens opportunities to better understand the mechanics and transport processes that occur in large-volume subcutaneous injections of mAbs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hector Gomez reports financial support was provided by Eli Lilly and Company. All co-authors reports financial support was provided by Eli Lilly and Company., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Viscoelastic flows are pervasive in a host of natural and industrial processes, where the emergence of nonlinear and time-dependent dynamics regulates flow resistance, energy consumption, and particulate dispersal. Polymeric stress induced by the advection and stretching of suspended polymers feeds back on the underlying fluid flow, which ultimately dictates the dynamics, instability, and transport properties of viscoelastic fluids. However, direct experimental quantification of the stress field is challenging, and a fundamental understanding of how Lagrangian flow structure regulates the distribution of polymeric stress is lacking. In this work, we show that the topology of the polymeric stress field precisely mirrors the Lagrangian stretching field, where the latter depends solely on flow kinematics. We develop a general analytical expression that directly relates the polymeric stress and stretching in weakly viscoelastic fluids for both nonlinear and unsteady flows, which is also extended to special cases characterized by strong kinematics. Furthermore, numerical simulations reveal a clear correlation between the stress and stretching field topologies for unstable viscoelastic flows across a broad range of geometries. Ultimately, our results establish a connection between the Eulerian stress field and the Lagrangian structure of viscoelastic flows. This work provides a simple framework to determine the topology of polymeric stress directly from readily measurable flow field data and lays the foundation for directly linking the polymeric stress to flow transport properties.

Background: Lifestyle risk factors, such as obesity, physical inactivity, smoking, and having an unhealthy diet are significantly associated to the risk of developing metabolic diseases such as type 2 diabetes, insulin resistance, and metabolic syndrome (MetS). Consequently, it is important to examine multiple lifestyle risk factors instead of single ones. Moreover, the combined effects of these factors on risk of MetS are not fully investigated. This study investigated the relationship between HLS and MetS and its components among apparently healthy adults living in Tabriz-Iran., Methods: This cross-sectional study includes 347 apparently healthy adults aged 20-50. To assess healthy lifestyle, four habits were used to examine HLS: physical activity (PA), smoking, healthy eating index-2015 (HEI-2015), and body mass index (BMI). Smoking status, PA, and dietary intakes (147-item) of study participants were evaluated using valid questionnaires. The lifestyle score ranged from zero (non-healthy) to four (most healthy) points. Binary logistic regression with adjusted models was used to examine the association of HLS and MetS, and its components. P < 0.05 was considered statistically significant., Results: In the current study, the average age and BMI of study participants were 40.78 ± 9.23 years old and 29.23 ± 5.97 kg/m 2 , respectively. Participants in the highest quartile of HLS had significantly lower waist circumference (WC), BMI, weight, and had less fasting blood sugar (FBS), and triglyceride (TG) compared to the lowest quartile of HLS. Individuals in the second quartile of HLS had 24% greater odds for having MetS compared with those in the first quartile (adjusted OR: 1.24; 95% CI: 1.05-2.66). A significant reduction in hyperglycemia (adjusted OR: 0.85, 95% CI: 0.55-0.96) and high TG (adjusted OR: 0.83; 95% CI: 0.55-0.93) risk was also observed in the highest category of HLS compared to the lowest category. Moreover, after taking potential confounders into account, low score of HLS was associated with increased odds of MetS in women (adjusted OR: 1.32; 95% CI: 1.03-2.91)., Conclusion: The results showed that the lowest adherence to HLS was associated with higher odds MetS in women, after adjusting for all covariates. Moreover, adherence to a healthy lifestyle was related to lower odds of hyperglycemia and high TG in Iranian adults. To confirm these results, prospective studies are required., (© 2023. The Author(s).)

Machine learning methods can be used as robust techniques to provide invaluable information for analyzing biological samples in pharmaceutical industries, such as predicting the concentration of viral particles of interest in biological samples. Here, we utilized both convolutional neural networks (CNNs) and random forests (RFs) to predict the concentration of the samples containing measles, mumps, rubella, and varicella-zoster viruses (ProQuad®) based on Raman and absorption spectroscopy. We prepared Raman and absorption spectra data sets with known concentration values, then used the Raman and absorption signals individually and together to train RFs and CNNs. We demonstrated that both RFs and CNNs can make predictions with R 2 values as high as 95%. We proposed two different networks to jointly use the Raman and absorption spectra, where our results demonstrated that concatenating the Raman and absorption data increases the prediction accuracy compared to using either Raman or absorption spectrum alone. Additionally, we further verified the advantage of using joint Raman-absorption with principal component analysis. Furthermore, our method can be extended to characterize properties other than concentration, such as the type of viral particles., (© 2022 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Accurate injection time prediction is essential in developing spring-driven autoinjector devices since the drug delivery is expected to finish within seconds to bring convenience, reduce the risk for early lift-off, and provide a consistent experience to users. The Carreau model captures the liquid's shear-dependent viscosity measured in our experiments. Thus, a quasi-steady model, which uses the Carreau model to describe the liquid's viscosity, is developed to predict the injection time of spring-driven autoinjectors. Analytical relations between the flow rate and the pressure drop in the needle are also obtained. The Carreau number in the spring-driven autoinjector is greater than one and smaller than a critical value; in this region, using the power-law model to describe the liquid viscosity accurately predicts the injection time, which agrees with the current literature findings. Additionally, a force threshold is identified for the friction force between the plunger and the syringe barrel, beyond which the injection time is infinite. Appreciation of this force threshold can help avoid device stalling and reduce the risk of underdosing. Moreover, the role of liquid's shear-thinning index on the injection time of spring-driven autoinjectors is quantified. Understanding the shear-thinning index allows formulators to experiment with excipients and pH to enhance confidence in drug/device combination product design and integration. Our experimental and theoretical results can help drug product and device developers with integrated product design and improve the patient experience., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Metabolic syndrome (MetS) is one of the most significant public health issues worldwide, and diet quality is an important controllable environmental factor influencing the incidence of MetS. Numerous dietary scores have been established to assess compliance with dietary recommendations or eating patterns, many of which are not entirely food-based. Hence, Lifelines Diet Score (LLDS) was developed in response to the shortcomings of existing tools. This study aimed to assess any possible links between total food quality and cardiometabolic risk factors among overweight and obese adults., Methods: This cross-sectional study included 338 overweight and obese individuals [body mass index (BMI) > 25 kg/m 2 ] aged 20-50 years in Tabriz, Iran. To collect dietary data, we used a validated semi-quantitative Food Frequency Questionnaire (FFQ) for Iranian population. Enzymatic-colorimetric methods were used to assess serum glucose and lipids, and enzyme-linked immunosorbent assay (ELISA) kits were used to measure insulin levels. In addition, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated., Results: BMI and hip circumference (HC) were significantly different ( P < 0.05) amongst LLDS tertiles. Adherence to the highest tertile of LLDS was associated with lower SBP, and the subjects in higher LLDS tertiles significantly had lower systolic blood pressure (SBP) ( P = 0.04). Triglyceride (TG) levels were also lower in the third tertile of LLDS with a near-significant P -value ( P = 0.05)., Conclusion: According to our results, a higher diet quality score, determined by LLDS, can be associated with a lower risk of MetS. Further experimental and longitudinal studies are needed to better understand this relationship., 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 Akhavanfar, Hojati, Kahrizi, Farhangi and Ardekani.)

Understanding the interface motion and hydrodynamic shear induced by the liquid sloshing during the insertion stage of an autoinjector can help improve drug product administration. We perform experiments to investigate the interfacial motion and hydrodynamic shear due to the acceleration and deceleration of syringes. The goal is to explore the role of fluid properties, air gap size, and syringe acceleration on the interface dynamics caused by autoinjector activation. We used a simplified autoinjector platform to record the syringe and liquid motion without any view obstruction. Water and silicone oil with the same viscosity are used as the model fluids. Particle Image Velocimetry (PIV) is employed to measure the velocity field. Simultaneous shadowgraph visualization captures the air entrainment. Our in-house PIV and image processing algorithms are used to quantify the hydrodynamic stress and interfacial area to investigate the effects of various autoinjector design parameters and fluid types on liquid sloshing. The results indicate that reducing the air gap volume and syringe acceleration/deceleration mitigate the interface area and effective shear. Moreover, the interfacial area and induced hydrodynamic stress decrease with the Fr=U/aD, where U is the interface velocity, a is the maximum syringe acceleration, and D is the syringe diameter., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Lung cancer is the leading cause of cancer-related death worldwide, with non-small-cell lung cancer (NSCLC) being the primary type. Unfortunately, it is often diagnosed at advanced stages, when therapy leaves patients with a dismal prognosis. Despite the advances in genomics and proteomics in the past decade, leading to progress in developing tools for early diagnosis, targeted therapies have shown promising results; however, the 5-year survival of NSCLC patients is only about 15%. Low-dose computed tomography or chest X-ray are the main types of screening tools. Lung cancer patients without specific, actionable mutations are currently treated with conventional therapies, such as platinum-based chemotherapy; however, resistances and relapses often occur in these patients. More noninvasive, inexpensive, and safer diagnostic methods based on novel biomarkers for NSCLC are of paramount importance. In the current review, we summarize genomic and proteomic biomarkers utilized for the early detection and treatment of NSCLC. We further discuss future opportunities to improve biomarkers for early detection and the effective treatment of NSCLC.

Background: The dietary glycemic index (GI) has been introduced as a novel index to elucidate the potential of foods to increase postprandial glucose. According to the limited available data about the association of GI with cardio-metabolic risk factors such as lipid profile, blood glucose markers, and blood pressure in developing countries, the current study was conducted to investigate this association in apparently obese individuals., Method and Material: Three hundred forty-seven obese adults were recruited in the present cross-sectional study. A validated 147-food item semi-quantitative food frequency questionnaire (FFQ) was used to evaluate the usual dietary intake of study participants. Dietary GI was calculated using the international GI database. Fatty acid desaturase (FADs)2 gene variants were determined according to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). ANOVA was used to compare study variables across different tertile of GI., Results: We found significant differences in terms of anthropometric parameters [weight (P = 0.038), waist circumference (WC) (P = 0.023), weight to hip ratio (WHR) (P = 0.007), and fat-free mass (FFM) (P < 0.001)] between different tertiles of GI. Similarly, energy and macronutrient intakes had a significant difference across dietary GI, and subjects with a higher dietary intake of energy and macronutrients (carbohydrate, protein, and total fat) were assigned to the third tertile of dietary GI (P < 0.001). While there was no significant difference in terms of cardio-metabolic risk factors in different dietary GI tertiles. Moreover, the total GI score was non-significantly higher in the TT genotype of FADS2 gene polymorphism compared with other genotypes. While no significant difference was observed between FADS2 genotype frequencies in different GI tertiles., Conclusion: Calculated dietary GI was associated with several cardio-metabolic risk factors in obese individuals. However, further prospective studies and clinical trials are needed to confirm our findings., (© 2022. The Author(s).)

The subcutaneous injection is the main route of administration for monoclonal antibodies (mAbs) and several other biotherapeutics due to the patient comfort and cost-effectiveness. However, their transport and distribution after subcutaneous injection is poorly understood. Here, we exploit a three-dimensional poroelastic model to find the biomechanical response of the tissue, including interstitial pressure and tissue deformation during the injection. We quantify the drug concentration inside the tissue. We start with a single-layer model of the tissue. We show that during the injection, the difference between the permeability of the solvent and solute will result in a higher drug concentration proportional to the inverse permeability ratio. Then we study the role of tissue layered properties with primary layers, including epidermis, dermis, subcutaneous (SQ), and muscle layers, on tissue biomechanical response to injection and drug transport. We show that the drug will distribute mainly in the SQ layer due to its lower elastic moduli. Finally, we study the effect of secondary tissue elements like the deep fascia layer and the network of septa fibers inside the SQ tissue. We use the Voronoi tessellation algorithm to create random geometry of the septa network. We show how drugs accumulate around these tissue components as observed in the experimental SQ injection. Next, we study the effect of injection rate on drug concentration. We show how higher injection rates will slightly increase the drug concentration around septa fibers. Finally we demonstrate how the concentration dependent viscosity will increase the concentration of biotherapeutics in the direction of septa fibers., Competing Interests: Declaration of Competing Interest One or more of the authors of this paper have disclosed potential or pertinent conflicts of interest, which may include receipt of payment, either direct or indirect, institutional support, or association with an entity in the biomedical field which may be perceived to have potential conflict of interest with this work. For full disclosure statements refer to https://doi.org/10.1016/j.ijpharm.2022.122125. ER is research assistants and AMA and HG are professors in Mechanical Engineering at Purdue University., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Cavitation is an undesired phenomenon that may occur in certain types of autoinjectors (AIs). Cavitation happens because of rapid changes of pressure in a liquid, leading to the formation of small vapor-filled cavities, which upon collapsing, can generate an intense shock wave that may damage the device container and the protein drug molecules. Cavitation occurs in the AI because of the syringe-drug relative displacement as a result of the syringe's sudden acceleration during needle insertion and the ensuing pressure drop at the bottom of the container. Therefore, it's crucial to analyze the potential effect of cavitation on AI. The goal of the current study is to investigate the effects of syringe and AI design parameters such as air gap size, syringe filling volume, fluid viscosity, and drive spring force (syringe acceleration) on the risk and severity of cavitation., Methods: A model autoinjector platform is built to record the syringe and cavitation dynamics which we use to estimate the cavitation intensity in terms of extension rate and to study the effects of design parameters on the severity of cavitation., Results: Our results show the generation of an intense shock wave and a high extension rate upon cavitation collapse. The induced extension rate increases with syringe acceleration and filling volume and decreases with viscosity and air gap size., Conclusion: The most severe cavitation occurred in an AI device with the larger drive spring force and the syringe of a smaller air gap size filled with a less viscous fluid and a larger filling volume., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recent studies have provided evidence for tumor suppressive function of the embryonic stem cell-specific miR-302/367 cluster through induction of a reprogramming process. Aspirin has been found to induce reprogramming factors of mesenchymal-to-epithelial transition in breast cancer cells. Therefore, we aimed to investigate whether overexpression of miR-302/367 cluster and aspirin treatment cooperate in the induction of reprogramming and tumor suppression in breast cancer cells. MDA-MB-231 and SK-BR-3 human breast cancer cell lines were transfected with a miR-302/367 expressing vector and treated with aspirin. The cells were evaluated for indices of apoptosis, proliferation, migration, and invasion. In both cell lines, treatment of miR-302/367-transfected cells with aspirin upregulated expression of some main pluripotency factors such as OCT4, SOX2, NANOG, and KLF4, and downregulated expression of some invasion and angiogenesis markers at gene and protein levels. Aspirin increased the apoptotic rate in both cell lines transfected with miR-302/367. Both miR-302/367 and aspirin upregulated the expression of FOXD3 protein which is a known inducer of OCT4 and NANOG. Our results demonstrate that aspirin can enhance miR-302/367-induced reprogramming of breast cancer cells possibly through upregulation of FOXD3 expression. This can further augment the reversal of epithelial-mesenchymal transition and inhibits migration, invasion, and angiogenic signaling in breast cancer cells reprogrammed by miR-302/367. Therefore, aspirin may serve as a useful adjuvant for reprogramming of cancer cells., (© 2022 Wiley Periodicals LLC.)

The major challenges in the optimization of autoinjectors lie in developing an accurate model and meeting competing requirements. We have developed a computational model for spring-driven autoinjectors, which can accurately predict the kinematics of the syringe barrel, needle displacement (travel distance) at the start of drug delivery, and injection time. This paper focuses on proposing a framework to optimize the single-design of autoinjectors, which deliver multiple drugs with different viscosity. We replace the computational model for spring-driven autoinjectors with a surrogate model, i.e., a deep neural network, which improves computational efficiency 1,000 times. Using this surrogate, we perform Sobol sensitivity analysis to understand the effect of each model input on the quantities of interest. Additionally, we pose the design problem within a multi-objective optimization framework. We use our surrogate to discover the corresponding Pareto optimal designs via Pymoo, an open source library for multi-objective optimization. After these steps, we evaluate the robustness of these solutions and finally identify two promising candidates. This framework can be effectively used for device design optimization as the computation is not demanding, and decision-makers can easily incorporate their preferences into this framework., (Copyright © 2022 Elsevier B.V. All rights reserved.)