Expert Opinion About the Pharmacoeconomic Edge of Low-Cost Dapagliflozin in Type 2 Diabetes Mellitus in Indian Clinical Settings.

Background This study aimed to understand the attitudes, beliefs, and concerns of physicians across India regarding the economic burden of diabetes and subsequently the cost-effectiveness of low-cost dapagliflozin for the management of patients with uncontrolled type 2 diabetes mellitus (T2DM) on background metformin therapy in Indian clinical settings. Method A cross-sectional questionnaire survey was conducted among physicians treating people with T2DM with or without complications. The questions covered the general aspects of affordability and adherence to diabetes medications as well as specific details of low-cost dapagliflozin and its cost-effectiveness. Results In total, 844 physicians provided a response to the survey questionnaire. The physicians who participated in the study included diabetologists, endocrinologists, cardiologists, consulting physicians, and family physicians. A majority of the physicians (53%) opined that only 10%-30% of their patients can afford the cost of newer antidiabetic medicines, while 25% of the physicians mentioned that <10% of their patients had issues related to affordability. Further, 39% of the physicians opined that 20%-40% of their patients discontinue the medicines due to high cost. Most of the physicians (95%) agreed that due to the low cost of dapagliflozin, it can be used for the primary prevention of heart failure in patients with T2DM in India. Similarly, 98% of the physicians agreed that it can be used for the treatment of heart failure in patients with or without T2DM in India. A majority of these physicians (93%) responded that switching from expensive sodium/glucose cotransporter-2 inhibitors (SGLT2i) to low-cost dapagliflozin is a long-term cost-effective management of T2DM. In total, 98% of the physicians agreed that low-cost dapagliflozin has the characteristics of an ideal SGLT2i because of its metabolic benefits, cardioprotection, nephroprotection, and potential cost-effectiveness. Conclusion This survey-based study indicates that dapagliflozin is an effective and cost-saving therapy for patients with T2DM and complications. Low-cost dapagliflozin can revolutionize the treatment of T2DM in the Indian setting.

Competitive adsorption of multicomponent volatile organic compounds on biochar.

Crude oil contaminated lands are recognised to have significant contributions to airborne volatile organic compounds (VOCs) with adverse effects on human health and tropospheric ozone. Soil capping systems for controlling harmful emissions are critical engineering solutions where advanced soil remediation techniques are neither available nor feasible. Studies on the adsorption of single VOC species in biochar have shown promising results as a potential capping material; however, current understanding of mixed gas system and multi-component adsorption of VOCs on biochar which would represent more realistic in situ conditions is very limited. We present, for the first time, the results of a study on competitive adsorption of mixed VOCs, including aromatic and non-aromatic VOCs commonly emitted from crude oil contaminated sites on two types of biochar pyrolysed at 500°C from wheat straw and bagasse as feedstock. The kinetics of sorption of multicomponent VOCs including acetone, hexane, toluene and p-xylene in biochar are studied based on the results of an extensive experimental investigation using a bespoke laboratory setup. Both biochar types used in this study presented a high sorption capacity for VOC compounds when tested individually (51-110 mg/g). For the multicomponent mixture, the competition for occupying sorption sites on biochar surface resulted in a lower absolute sorption capacity for each species, however, the overall sorption capacity of biochar remained more or less similar to that observed in the single gas experiments (50-109 mg/g). The chemical interactions via hydrogen bonds, electrostatic attraction, and pore-filling were found to be the main mechanisms of adsorption of VOC in the biochar studied. The efficiency of biochar regeneration was assessed through five cycles of adsorption-desorption tests and was found to be between 88% and 96%. The incomplete desorption observed confirm the formation of likely permanent bonds and heel build-ups during the sorption process.

Sorption behaviour of xylene isomers on biochar from a range of feedstock.

Inland oil spillage is one of the widespread sources of crude oil volatile organic compound emissions (CVEs) for which the long-term remedial solutions are often complex and expensive. This paper investigates the potential of a low-cost containment solution for contaminated solids by volatile organic compounds (VOCs) using biochar. The results of an extensive experimental investigation are presented on the sorption kinetics of xylene isomers (one type of the most frequently detected CVEs) on commercial biochar produced by prevalent feedstocks (wheat, corn, rice and rape straw as well as hardwood) at affordable temperatures (300-500°C). Chemical and physical properties of biochar were analysed in terms of elemental composition, scanning electron microscopy, specific surface area, ATR-FTIR spectra and Raman spectrometry. We show that for high-temperature biochar with similar surface chemistry, the sorption efficiency is mainly controlled by porous structure and pore size distribution. Biochar samples with higher specific surface area and higher volume of mesopores showed the highest sorption capacity (45.37-50.88 mg/g) since the sorbate molecules have more access to active sites under a greater intra-particle diffusion and elevated pore-filling. P-xylene showed a slightly higher sorption affinity to biochar compared to other isomers, especially in mesoporous biochar, which can be related to its lower kinetic diameter and simpler molecular shape. The sorption capacity of biochar produced at higher pyrolysis temperatures was found to be more sensitive to changes in ambient temperature due to dominant physical adsorption. Elovich kinetic model was found to be the best model to describe xylenes' sorption on biochar which indirectly indicates π-π stacking and hydrogen bonding as the main mechanism of xylene sorption on these types of biochar.

Emissions of volatile organic compounds from crude oil processing - Global emission inventory and environmental release.

Airborne Volatile organic compounds (VOCs) are known to have strong and adverse impacts on human health and the environment by contributing to the formation of tropospheric ozone. VOCs can escape during various stages of crude oil processing, from extraction to refinery, hence the crude oil industry is recognised as one of the major sources of VOC release into the environment. In the last few decades, volatile emissions from crude oil have been investigated either directly by means of laboratory and field-based analyses, or indirectly via emission inventories (EIs) which have been used to develop regulatory and controlling measures in the petroleum industry. There is a vast amount of scattered data in the literature for both regional emissions from crude oil processing and scientific measurements of VOC releases. This paper aims to provide a critical analysis of the overall scale of global emissions of VOCs from all stages of oil processing based on data reported in the literature. The volatile compounds, identified via EIs of the crude oil industry or through direct emissions from oil mass, are collected and analysed to present a global-scale evaluation of type, average concentration and detection frequency of the most prevalent VOCs. We provide a critical analysis on the total averages of VOCs and key pieces of evidence which highlights the necessity of implementing control measures to regulate crude oil volatile emissions (CVEs) in primary steps of extraction-to-refinery pathways of crude oil processing. We have identified knowledge gaps in this field which are of importance to control the release of VOCs from crude oil, independent of oil type, location, operating conditions and metrological parameters.

Computational fluid dynamics in the microcirculation and microfluidics: what role can the lattice Boltzmann method play?

Patient-specific simulations, efficient parametric analyses, and the study of complex processes that are otherwise experimentally intractable are facilitated through the use of Computational Fluid Dynamics (CFD) to study biological flows. This review discusses various CFD methodologies that have been applied across different biological scales, from cell to organ level. Through this discussion the lattice Boltzmann method (LBM) is highlighted as an emerging technique capable of efficiently simulating fluid problems across the midrange of scales; providing a practical analytical tool compared to methods more attuned to the extremities of scale. Furthermore, the merits of the LBM are highlighted through examples of previous applications and suggestions for future research are made. The review focusses on applications in the midrange bracket, such as cell-cell interactions, the microcirculation, and microfluidic devices; wherein the inherent mesoscale nature of the LBM renders it well suited to the incorporation of fluid-structure interaction effects, molecular/particle interactions and interfacial dynamics. The review demonstrates that the LBM has the potential to become a valuable tool across a range of emerging areas in bio-CFD, such as understanding and predicting disease, designing lab-on-a-chip devices, and elucidating complex biological processes.

Computational hemodynamics of abdominal aortic aneurysms: Three-dimensional ultrasound versus computed tomography.

The current criterion for surgical intervention in abdominal aortic aneurysms, based upon a maximal aortic diameter, is considered conservative due to the high mortality rate in case of rupture. The research community is actively investigating the use of computational mechanics tools combined with patient-specific imaging to help identify more accurate criteria. Widespread uptake of a successful metric will however be limited by the need for computed tomography, which is at present the primary image extraction method on account of the location and complex shape of the aneurysms. The use of three-dimensional ultrasound as the scanning method is more attractive on account of increased availability, reduced cost and reduced risk to patients. The suitability of three-dimensional ultrasound is assessed for this purpose in the present work; computational fluid dynamics simulations were performed on geometries obtained from the same patient using both ultrasound and computed tomography. The influence of different smoothing algorithms is investigated in the geometry preparation stage and Taubin's low-pass filter was found to best preserve geometry features. Laminar, Newtonian, steady-state simulation analysis identified haemodynamic characteristics to be qualitatively similar in terms of wall shear stress, velocity and vorticity. The study demonstrates the potential for three-dimensional ultrasound to be integrated into a more accessible patient-specific modelling tool able to identify the need for surgical intervention of abdominal aortic aneurysms.

Application of a lattice Boltzmann-immersed boundary method for fluid-filament dynamics and flow sensing.

Complex fluid-structure interactions between elastic filaments, or cilia, immersed in viscous flows are commonplace in nature and bear important roles. Some biological systems have evolved to interpret flow-induced motion into signals for the purpose of feedback response. Given the challenges associated with extracting meaningful experimental data at this scale, there has been particular focus on the numerical study of these effects. Porous models have proven useful where cilia arrangements are relatively dense, but for more sparse configurations the dynamic interactions of individual structures play a greater role and direct modelling becomes increasingly necessary. The present study reports efforts towards explicit modelling of regularly spaced wall-mounted cilia using a lattice Boltzmann-immersed boundary method. Both steady and forced unsteady 2D channel flows at different Reynolds numbers are investigated, with and without the presence of a periodic array of elastic inextensible filaments. It is demonstrated that the structure response depends significantly on Reynolds number. For low Reynolds flow, the recirculation vortex aft of successive filaments is small relative to the cilia spacing and does not fully bridge the gap, in which case the structure lags the flow. At higher Reynolds number, when this gap is fully bridged the structure and flow move in phase. The trapping of vortices between cilia is associated with relatively lower wall shear stress. At low to intermediate Reynolds, vortex bridging is incomplete and large deflection is still possible, which is reflected in the tip dynamics and wall shear stress profiles.

Enhancing the Hydrophilicity and Cell Attachment of 3D Printed PCL/Graphene Scaffolds for Bone Tissue Engineering.

Scaffolds are physical substrates for cell attachment, proliferation, and differentiation, ultimately leading to the regeneration of tissues. They must be designed according to specific biomechanical requirements, i.e., certain standards in terms of mechanical properties, surface characteristics, porosity, degradability, and biocompatibility. The optimal design of a scaffold for a specific tissue strongly depends on both materials and manufacturing processes, as well as surface treatment. Polymeric scaffolds reinforced with electro-active particles could play a key role in tissue engineering by modulating cell proliferation and differentiation. This paper investigates the use of an extrusion-based additive manufacturing system to produce poly(ε-caprolactone) (PCL)/pristine graphene scaffolds for bone tissue applications and the influence of chemical surface modification on their biological behaviour. Scaffolds with the same architecture but different concentrations of pristine graphene were evaluated from surface property and biological points of view. Results show that the addition of pristine graphene had a positive impact on cell viability and proliferation, and that surface modification leads to improved cell response.

Skin equivalent tensional force alters keloid fibroblast behavior and phenotype.

Skin tension may influence keloid scar behavior, development, and spreading, e.g., butterfly-shaped keloid disease in the sternum. Here, we developed a three-dimensional (3D) in vitro model to mimic in vivo tension and evaluate keloid fibroblast (KF) behavior and extracellular matrix synthesis under tension. In vivo skin tension measured in volunteers (n = 4) using 3D image photogrammetry enabled prediction of actual force (35 mN). A novel cell force monitor applied tension in a fibroblast-populated 3D collagen lattice replicating the in vivo force. The effect of tension on keloid (n = 10) fibroblast (KF) and normal skin (n = 10) fibroblasts (NF) at set time points (6, 12, and 24 hours) was measured in Hsp27, PAI-2, and α2ß1 integrin, tension-related genes demonstrating significant (p < 0.05) time-dependent regulation of these genes in NF vs. KF with and without tension. KF showed higher (p < 0.05) proliferation post-tension. Knockdown of all three genes in 24 and 48 hours with and without tension showed significant down-regulation in NF vs. KF. Additionally, we show significant (p < 0.05) modification of the expression of extracellular matrix-related genes post-tension following down-regulation of Hsp27, PAI-2, or α2ß1 integrin. Finally, we demonstrate significant alteration in NF compared with KF morphology following knockdown. In conclusion, this study shows induction of tension-related genes expression following mechano-regulation in KFs, with potential relevance to its development and therapy.

Up-regulation of tension-related proteins in keloids: knockdown of Hsp27, α2ß1-integrin, and PAI-2 shows convincing reduction of extracellular matrix production.

BACKGROUND: Keloid disease is a fibroproliferative disorder, with an ill-defined treatment that is characterized by excessive extracellular matrix deposition. Mechanical tension promotes deposition of extracellular matrix and overexpression of tension-related proteins, which is associated with keloid disease. The aim of this study was to investigate the effect of tension-related proteins on extracellular matrix steady-state synthesis in primary keloid fibroblasts. METHODS: Keloid fibroblasts (n = 10) and normal skin (n = 4) fibroblast cultures were established from passages 0 to 3. A panel of 21 tension-related genes from microarray data were assessed at mRNA (quantitative reverse-transcriptase polymerase chain reaction) and protein (in-cell Western blotting) levels. Three genes were significantly altered in keloid tissue and fibroblasts, and their functional role was assessed using siRNA knockdown. RESULTS: Hsp27, α2ß1-integrin, and PAI-2 were significantly up-regulated (p < 0.05)in keloid tissue and fibroblasts compared with normal skin. Hsp27, α2ß1-integrin, and PAI-2 expression was inhibited by RNA interference. Both the mRNA and protein levels of Hsp27, α2ß1-integrin, and PAI-2 significantly decreased (p < 0.05) in keloid fibroblasts at 48 hours after transfection. After down-regulation of Hsp27, α2ß1-integrin, and PAI-2, the expression of intracellular extracellular matrix was significantly reduced (p < 0.05). Water-soluble tetrazolium salt-1 assay showed that transfection of Hsp27, α2ß1-integrin, and PAI-2 did not influence the viability/metabolic activity of keloid fibroblasts. CONCLUSIONS: This study demonstrates overexpression of key tension-related proteins in keloid tissue and keloid fibroblasts. Knockdown of Hsp27, PAI-2, and α2ß1-integrin by RNA interference attenuates the expression of mRNA and protein levels and certain other extracellular matrix molecules.

Optimization of the position of the acetabulum in a ganz periacetabular osteotomy by finite element analysis.

Periacetabular osteotomy (PAO) is a surgical procedure to correct acetabular orientation in developmental dysplasia of the hip (DDH). It changes the position of the acetabulum to increase femoral head coverage and distribute the contact pressure over the cartilage surface. The success of PAO depends significantly on the surgeon's experience. Using computed tomography data from patients with DDH, we developed a 3D finite element (FE) model to investigate the optimal position of the acetabulum following PAO. A virtual PAO was performed with the acetabulum rotated in increments from the original center edge (CE) angle. Contact area, contact pressure, and Von Mises stress in the femoral and pelvic cartilage were analyzed. Five dysplastic hips from four patients were modeled. Contact area, contact pressure, and Von Mises stress in the cartilage all varied according to the change of CE angle through virtual PAO. An optimal position could be achieved for the acetabulum that maximizes the contact area while minimizing the contact pressure and von Mises stress in the pelvic and femoral cartilage. The optimal position of the acetabulum was patient dependent and did not always correspond to what would be considered a "normal" CE angle. We demonstrated for the first time the interrelation of correction angle, contact area, and contact pressure between the pelvic and femoral cartilage in PAO surgery.

Differential cytotoxic response in keloid fibroblasts exposed to photodynamic therapy is dependent on photosensitiser precursor, fluence and location of fibroblasts within the lesion.

Treatment of keloid disease (KD) is ill-defined and remains challenging. We previously reported successful clinical application of photodynamic therapy (PDT) in KD. The aim here was to evaluate cytotoxic effect of PDT using methyl aminolevulinate (M-ALA) and 5-aminolevulinic acid (5-ALA) on keloid fibroblasts (KF) (n = 8) from different lesional sites (top, middle and margin) as compared to normal skin fibroblasts (n = 3). The effect of protoporphyrin IX (PpIX) precursors was evaluated by fluorescence emission, LDH and WST-1 assay, reactive oxygen species (ROS) generation and qRT-PCR analysis. Apoptosis/necrosis differentiation and senescence were studied by fluorometric staining with Hoechst 33258/propidium iodide and ß-galactosidase activity, respectively. Three hours post incubation with 4 mM precursors of photosensitisers, PpIX accumulation was site specific and higher with M-ALA. Cytotoxicity was also site specific (higher in fibroblasts from middle of the keloid as compared to cells from other sites) and increased proportionately to fluence rates post-PDT. Additionally, cytoproliferation was significantly decreased post-PDT depending on the light energy. Fluorescence analysis revealed that M-ALA instigated higher KF cytotoxicity at lower fluence (≤20 J/cm(2)) while 5-ALA instigated higher KF cytotoxicity at higher fluence, except in cells derived from middle of the keloid. ROS-mediated cytotoxicity was light energy dependent. Senescence was not observed at higher light energies (>10 J/cm(2)). Compared to other sites, fibroblasts from the middle were more prone to cell death post 5-ALA treatment. We conclude that cytotoxicity post-PDT in KD fibroblasts is dependent on the lesional site, precursor of intracellular photosensitiser and fluence. Thus, PDT may be used for site-targeted therapy of KD.

Changes in the stress in the femoral head neck junction after osteochondroplasty for hip impingement: a finite element study.

The surgical treatment of femoroacetabular impingement (FAI) often involves femoral osteochondroplasty. One risk of this procedure is fracture of the femoral neck. We developed a finite element (FE) model to investigate the relationship between depth of resection and femoral neck stress. CT data were used to obtain the geometry of a typical cam-type hip, and a 3D FE model was constructed to predict stress in the head-neck after resection surgery. The model accounted for the forces acting on the head and abductor muscular forces. Bone resection was performed virtually to incremental resection depths. The stresses were calculated for five resection depths and for five different activities (i) standing on one leg (static case); (ii) two-to-one-to-two leg standing; (iii) normal walking; (iv) walking down stairs; and (v) a knee bend. In general, both the average Von Mises stresses and the area of bone that yielded significantly increased at a resection depth of ≥10 mm. The knee bend and walking down stairs demonstrated the highest stresses. The FE model predicts that fracture is likely to occur in the resection area first following removal of a third (10 mm) or more of the diameter of the femoral neck. We suggest that when surgeons perform osteochondroplasty for hip impingement, the depth of resection should be limited to 10 mm.