In silico dose adjustment of levothyroxine after total thyroidectomy using fuzzy logic methodology: A proof-of-concept study.

Thyroid hormone replacement therapy is used to raise undesirably low concentrations of natural thyroid hormones, commonly by administrating levothyroxine (LT4). Finding the appropriate LT4 dose regime, particularly for patients undergone thyroidectomy, is still demanding more effort, and much research has been conducted. Providing a new fuzzy logic system, a useful control algorithm, we aim to introduce a proper LT4 dosing regimen for every thyroidectomized patient in a computerized environment. Consequently, we contrast the differences between our proposed dose regime and conventional monotherapy methods using THYROSIM, a thyroid simulation application. Considering our nine defined comparative criteria, results reveal that the FLS dose regime is dominant in terms of six indexes, while the discrepancies are not noticeable in the other three indexes. A great superiority of FLS dose regime is its ability to reduce the time to reach desirable thyrotropin (Thyroid Stimulating Hormone, TSH) serum concentration to 6 days post-thyroidectomy, and keep the T4, T3, and TSH values in the normal window afterward. The proposed FLS could be an applicable decision support system for physicians as they can define their intended Individual Target Value of TSH for each patient to optimize LT4 dose adjustment.

Phenomenological characterization of blood's intermediate shear rate: a new concept for hemorheology.

The phenomena of aggregation, breakdown, and disaggregation of the rouleaux of red blood cells (RBCs) in addition to deformability affect the human blood viscosity at different shear rates. In this study, the intermediate shear rate is introduced and defined when the effect of aggregation on the change of blood viscosity is diminished; and afterwards, the alteration in the blood viscosity is dominantly affected by the deformation of RBCs. With this respect, modeling the effective parameters on the blood shear-thinning behavior including hematocrit and plasma viscosity was performed for the two different shear regions discriminated by the proposed intermediate shear rates. The presented rheological model reflects a phenomenological approach to assess the human blood viscosity with an average error of ± 5% compared to experimental data for hematocrits between 0.299 and 0.702, subjected to various shear rates from 0.2 to 680 1/s. The temperature changes as well as biochemical effects on whole blood viscosity are characterized by the introduced plasma viscosity-dependent model. The presented comprehensive model could be used for better understanding of blood flow hemodynamics and analyzing the shear dependence of aggregation and deformability behaviors of RBCs.

Elimination of Induced Hypoxic Regions in Depth of 3D Porous Silk Scaffolds by the Introduction of Channel Configuration.

Development of large, clinically sized tissue constructs with efficient mass transport is a tremendous need in tissue engineering. One major challenge in large tissue-engineered constructs is to support homogeneous delivery of oxygen and nutrients throughout the tissue scaffold while eliminating induced hypoxic regions in depth. To address this goal, we introduced an especial channeled architecture on porous silk-based tissue scaffolds to improve supplying of oxygen to the cells in central regions of the scaffolds. Oxygen gradients were measured and evaluated in three scaffold prototypes, namely, one unchanneled and two channeled scaffolds with different channel diameters (500 µm and 1000 µm). The channels were introduced into the constructs using stainless-steel rods arranged uniformly in stainless-steel mold, a fabrication method that enables precise control over channel diameter and the distance between channels. During 2-week culture of G292 cells, the 1000 µm channeled scaffolds demonstrated higher oxygen concentration at the center compared to 500 µm channeled prototype; however, the oxygen concentration approached the same level around the last days of culture. Nevertheless, homogenous oxygen distribution throughout the 1000 µm channeled constructs and the consequence of higher cell proliferation at day 14 postseeding corroborate the efficient elimination of induced hypoxic regions; and therefore, it holds promise for clinically relevant sized scaffold especially in bone tissue engineering.

Cerium functionalized graphene nano-structures and their applications; A review.

Graphene-based nanomaterials with remarkable properties, such as good biocompatibility, strong mechanical strength, and outstanding electrical conductivity, have dramatically shown excellent potential in various applications. Increasing surface area and porosity percentage, improvement of adsorption capacities, reduction of adsorption energy barrier, and also prevention of agglomeration of graphene layers are the main advantages of functionalized graphene nanocomposites. On the other hand, Cerium nanostructures with remarkable properties have received a great deal of attention in a wide range of fields; however, in some cases low conductivity limits their application in different applications. Therefore, the combination of cerium structures and graphene networks has been widely invesitaged to improve properties of the composite. In order to have a comprehensive information of these nanonetworks, this research reviews the recent developments in cerium functionalized graphene derivatives (graphene oxide (GO), reduced graphene oxide (RGO), and graphene quantum dot (GQD) and their industrial applications. The applications of functionalized graphene derivatives have also been successfully summarized. This systematic review study of graphene networks decorated with different structure of Cerium have potential to pave the way for scientific research not only in field of material science but also in fluorescent sensing, electrochemical sensing, supercapacitors, and catalyst as a new candidate.

Development of Hormonal Intravaginal Rings: Technology and Challenges.

Intravaginal rings (IVRs) are minimally invasive polymeric devices specifically designed to be used for the sustained and prolonged release of various type of drugs such as hormones. One of the benefits of using topical drug delivery systems (e.g., IVRs) is the fact that systemic drug delivery may cause drug resistance due to elevated drug levels. Topical drug delivery also provides higher concentrations of the drug to the target site and has fewer side effects. In addition, when a drug is administered vaginally, the hepatic first-pass effect is avoided, resulting in higher absorption. Contraception and treatments for specific diseases such as endometriosis and hormone deficiencies can be improved by the administration of hormones via an IVR. This article aims to classify and compare various designs of commercially available and non-commercial hormonal IVRs and to analyze their performance. Current challenges affecting the development of IVRs are investigated, and proposed solutions are discussed. A comprehensive search of publications in MEDLINE/PubMed and of commercial product data of IVRs was performed, and the materials, designs, performance, and applications (e.g., contraception, endometriosis, estrogen deficiency and urogenital atrophy) of hormonal IVRs were thoroughly evaluated. Most hormonal IVRs administer female sex hormones, i.e., estrogen and progestogens. In terms of material, IVRs are divided into 3 main groups: silicone, polyurethane, and polyethylene-co-vinyl acetate IVRs. As regards their design, there are 4 major designs for IVRs which strongly affect their performance and the timing and rate of hormone release. Important challenges include reducing the burst release and maintaining the bioavailability of hormones at their site of action over a prolonged period of administration as well as lowering production costs. Hormonal IVRs are a promising method which could be used to facilitate combination therapies by administering multiple drugs in a single IVR while eliminating the side effects of conventional drug administration methods. IVRs could considerably improve women's quality of life all over the world within a short period of time.

Sustained subconjunctival drug delivery systems: current trends and future perspectives.

PURPOSE: One of the challenges of ocular drug delivery systems is sustainable delivery of the intended drug to the posterior segment of the eye. Periocular routes of drug delivery are a promising method to bridge this challenge. The purpose of this study is to investigate the recent advances and potentials of subconjunctival route and its pros and cons in comparison with other ocular drug delivery routes. METHODS: In this literature review, the comprehensive search of publications was performed in MEDLINE/PubMed indicating investigations on subconjunctival drug delivery systems using relevant keywords. RESULTS: Based on the resultant detailed criteria to choose an appropriate ocular drug delivery route, it is revealed that most of these routes are either highly invasive and/or provide low bioavailability of drug to the target tissue. Nevertheless, subconjunctival drug delivery could be considered as one of the less invasive and easily accessible routes for delivering various drugs to both anterior and posterior segments of the eye. However, most of such researches are at the stage of animal study in their pipelines. CONCLUSION: Periocular route of drug delivery is one of the most efficient routes for delivering the drugs to both anterior and posterior segments of the eye. Subconjunctival sustained drug delivery is highly effective and less invasive compared to other periocular routes. This makes subconjunctival implants and injections one of the most proper ways of treating various ranges of ocular diseases and disorders, e.g., diabetic retinopathy, dry eye syndrome, glaucoma, etc.

Starch nanoparticle as a vitamin E-TPGS carrier loaded in silk fibroin-poly(vinyl alcohol)-Aloe vera nanofibrous dressing.

Core-sheath nanofibrous mat as a new vitamin E (VE) delivery system based on silk fibroin (SF)/poly(vinyl alcohol) (PVA)/aloe vera (AV) was successfully prepared by the electrospinning method. Initially, VE-loaded starch nanoparticles were produced and then incorporated into the best beadless SF-PVA-AV nanofibers. The successful loading of VE in starch nanoparticles was proved by Fourier-transform infrared spectroscopy. The scanning electron microscopy and transmission electron microscopy indicated that spherical nanoparticles were successfully embedded within the nanofibers. In vitro release studies demonstrated that the release of VE was controlled by Fickian diffusion and was faster in samples containing more nanoparticles. Fibroblast attachment, proliferation, and collagen secretion were enhanced after adding AV and VE to the SF-PVA nanomatrix. Moreover, the incorporation of VE into the nanocomposite dressing enhanced antioxidant activity, which can have a positive effect on wound healing process by protecting the cells from toxic oxidation products.

A new approach for semiempirical modeling of mechanical blood trauma.

PURPOSE: Two semi-empirical models were recently published, both making use of existing literature data, but each taking into account different physical phenomena that trigger hemolysis. In the first model, hemoglobin (Hb) release is described as a permeation procedure across the membrane, assuming a shear stress-dependent process (sublethal model). The second model only accounts for hemoglobin release that is caused by cell membrane breakdown, which occurs when red blood cells (RBC) undergo mechanically induced shearing for a period longer than the threshold time (nonuniform threshold model). In this paper, we introduce a model that considers the hemolysis generated by both these possible phenomena. METHODS: Since hemolysis can possibly be caused by permeation of hemoglobin through the RBC functional membrane as well as by release of hemoglobin from RBC membrane breakdown, our proposed model combines both these models. An experimental setup consisting of a Couette device was utilized for validation of our proposed model. RESULTS: A comparison is presented between the damage index (DI) predicted by the proposed model vs. the sublethal model vs. the nonthreshold model and experimental datasets. This comparison covers a wide range of shear stress for both human and porcine blood. An appropriate agreement between the measured DI and the DI predicted by the present model was obtained. CONCLUSIONS: The semiempirical hemolysis model introduced in this paper aims for significantly enhanced conformity with experimental data. Two phenomenological outcomes become possible with the proposed approach: an estimation of the average time after which cell membrane breakdown occurs under the applied conditions, and a prediction of the ratio between the phenomena involved in hemolysis.

Relation of Stroke Risk Factors with Specific Stroke Subtypes and Territories.

BACKGROUND: Although the risk factors of ischemic strokes are well defined, there is slight information about their relations with the etiologies of ischemic strokes. This study investigated the distribution of ischemic stroke risk factors and their connections to diverse etiologies of cerebrovascular attack (CVA) and specific ischemic regions of brain. METHODS: In this cross sectional study, we analyzed the data of patients with definite diagnosis of CVA, excluding hemorrhagic strokes, registered in Imam Hossein Medical Center in Tehran, Iran. The data were collected from entire archived medical records from March 2010 until September 2012, retrospectively. RESULTS: Out of 1696 cases a total of 1011 subjects, 487 (48.2%) males and 524 (51.8%) females with mean age of 68.91±13.54 yr were included in the study. Patients suffering from atrial fibrillation (AF), valvular heart disease (VHD), and dilated cardiomyopathy were more prone to develop cardioembolic stroke. Those with diabetes mellitus (DM), carotid artery stenosis and dyslipidemia (DLP) had a higher prevalence of macroangiopathic stroke. Ischemic heart disease (IHD), AF, and VHD were associated with stroke in the brain territory supplied by middle cerebral artery (MCA) while DM and carotid artery stenosis were correspondent with posterior cerebral artery (PCA) stroke. CONCLUSION: The diagnosis of the weight of each risk factor of ischemic strokes on different etiologies and territories of ischemia can assist care providers for a more efficient prevention of strokes. The results of this study can also be a basis for further investigations to corroborate the pathophysiology of such relations.

Simulation of blood oxygenation in capillary membrane oxygenators using modified sulfite solution.

Blood oxygenation is the main performance characteristic of capillary membrane oxygenators (CMOs). Handling of natural blood in in vitro investigations of CMOs is quite complex and time-consuming. Since the conventional blood analog fluids (e.g. water/glycerol) lack a substance with an affinity to capture oxygen comparable to hemoglobin's affinity, in this study a novel approach using modified sulfite solution is proposed to address this challenge. The solution comprises sodium sulfite as a component, simulating the role of hemoglobin in blood oxygenation. This approach is validated by OTR (oxygen transfer rate) measured using native porcine blood, in two types of commercially available CMOs. Consequently, the number of complicated natural blood investigations in the evolution procedure of newly developed oxygenators would considerably decrease. Moreover, the reassessing of failed devices, in clinics, would be performed more precisely using a modified sulfite solution than simple water/glycerol testing.

Engineering parameters in bioreactor's design: a critical aspect in tissue engineering.

Bioreactors are important inevitable part of any tissue engineering (TE) strategy as they aid the construction of three-dimensional functional tissues. Since the ultimate aim of a bioreactor is to create a biological product, the engineering parameters, for example, internal and external mass transfer, fluid velocity, shear stress, electrical current distribution, and so forth, are worth to be thoroughly investigated. The effects of such engineering parameters on biological cultures have been addressed in only a few preceding studies. Furthermore, it would be highly inefficient to determine the optimal engineering parameters by trial and error method. A solution is provided by emerging modeling and computational tools and by analyzing oxygen, carbon dioxide, and nutrient and metabolism waste material transports, which can simulate and predict the experimental results. Discovering the optimal engineering parameters is crucial not only to reduce the cost and time of experiments, but also to enhance efficacy and functionality of the tissue construct. This review intends to provide an inclusive package of the engineering parameters together with their calculation procedure in addition to the modeling techniques in TE bioreactors.

Novel concept for pure diffusive capillary membrane oxygenators: silicone hollow sphere (SiHSp) fibers.

The preeminent limitation of silicone membrane oxygenators is the poor gas permeability compared with microporous hollow fiber oxygenators (MHFO). However, the imponderability of plasma leakage, foam formation, and brittleness are all hazards that result in blood trauma formation, hereby limiting the application of MHFO during long-term oxygenation therapies. Here, we introduce a novel type of pure diffusive capillary-form silicone membrane called silicone hollow sphere. Silicone hollow sphere walls embed hollow microspheres into the core. The lodging of such microspheres promotes a higher gas exchange performance (as a result of the reduction of dense material) without altering the total thickness of capillary walls; thereby the demanded mechanical strength for handling is nevertheless conserved. Out of the same silicone material, seven SiHSp fibers with six different design specifications and a control were constructed to define experimentally the appropriate configuration for subsequent production. Each fiber was used in a miniaturized module oxygenator of a constant effective membrane surface area (Amem = 0.02 m) and length (L =183 mm) for a fair evaluation. Modules were investigated in vitro with porcine blood. O2 and CO2 transfer rates weighed 12.6 mlO2/min and 10.4 mlCO2/min, respectively, for one type of SiHSp, comparable with microporous polypropylene (OXYPHAN) exhibiting 14.1 mlO2/min and 13.2 mlCO2/min, respectively, at a maximum blood flow rate (Qmax = 200 ml/min). Silicone hollow sphere fibers show a promising competency to MHFs. They also show an evident dominancy over the conventional silicone fibers, evaluated by the control module, which emphasizes the advantage of this design.

A theoretical model for evaluation of the design of a hollow-fiber membrane oxygenator.

Geometric data are fundamental to the design of a contactor. The efficiency of a membrane contactor is mainly defined by its mass-transfer coefficient. However, design modifications also have significant effects on the performance of membrane contactors. In a hollow-fiber membrane oxygenator (HFMO), properties such as priming volume and effective membrane surface area (referred to as design specifications) can be determined. In this study, an extensive theoretical model for calculation of geometric data and configuration properties, and, consequently, optimization of the design of an HFMO, is presented. Calculations were performed for Oxyphan(®) hollow-fiber micro-porous membranes, which are frequently used in current HFMOs because of their high gas exchange performance. The results reveal how to regulate both the transverse and longitudinal pitches of fiber bundles to obtain a lower rand width and a greater number of windings. Such modifications assist optimization of module design and, consequently, substantially increase the efficiency of an HFMO. On the basis of these considerations, three values, called efficiency factors, are proposed for evaluation of the design specifications of an HFMO with regard with its performance characteristics (i.e. oxygen-transfer rate and blood pressure drop). Moreover, the performance characteristics of six different commercial HFMOs were measured experimentally, in vitro, under the same standard conditions. Comparison of calculated efficiency factors reveals Quadrox(®) is the oxygenator with the most efficient design with regard with its performance among the oxygenators tested.