Is canagliflozin effective in lowering the risk of all-cause mortality in adults with type 2 diabetes compared to the placebo?

OBJECTIVE: The objective of this selective EBM review is to determine whether or not “canagliflozin is effective in lowering the risk of all-cause mortality in adults with type 2 diabetes compared to the placebo?” STUDY DESIGN: A systematic review of three English language, primary, double-blind, randomized controlled trials published from 2013 to 2019. DATA SOURCES: All primary studies were published in peer reviewed journals and selected through PubMed and Cochrane databases comparing canagliflozin vs. placebo. OUTCOMES MEASURED: All-cause mortality, defined as death of patient within the study interval and expressed as number of death/ total participants over the study time interval. RESULTS: The search yielded a total of 20 articles. Three studies were ultimately included in the EBM review after exclusion of other irrelevant studies. Neal et al. showed no statistically significant reduction in all-cause mortality rate, 17.3 vs. 19.5 participants with an event per 1000 patient-years between the intervention vs. placebo groups, respectively (HR 0.87; 95% CI 0.74 to 1.01; P = 0.24). In the Perkovic study, all-cause mortality rate was also similar between both groups, 29.0 vs. 35.0 per 1000 patient-years (HR 0.83; 95% CI 0.68–1.02; P not given) for the intervention and placebo groups, respectively. Likewise, all-cause mortality rate was shown to be the same, 1.1 % in both the placebo and the treatment arms in Yale et al. study. CONCLUSIONS: The results of all three studies demonstrated that canagliflozin is not effective in lowering the risk of all-cause mortality in adults with type 2 diabetes compared to the matched placebo. Due to the potential heterogeneity among the included studies, the results of this analysis should be confirmed with new and larger trials in the future to better evaluate all-cause mortality over a longer follow-up period

Dry Eye Therapy Using Cannabinoid Ligands

Dry eye disease (DED) has a high prevalence (up to 50% in some communities) with increasing incidence. Notably, patients have such high morbidity and burden that they desperately need effective treatment. However, as a "multifactorial disease," DED consists of various complex disorders, all of which interact to form a vicious circle and obscure the etiology. Even though physicians and patients have different therapeutic options, the common disadvantages in current treatments are (i) a lack of compliance due to an overload of products, (ii) the occurrence of side effects of different drugs, and (iii) limited efficiency in some particular cases. As a result, DED requires a novel therapy capable of simultaneously addressing multiple targets in DED pathogenesis. To find suitable targets and candidates for DED, the endocannabinoid system (ECS) and its receptors (CBRs) present at the ocular surface are a promising choice, as ECS functions are involved in a plethora of physical processes. Experimental evidence showed that using CBRs ligands can modulate anti-inflammatory, neurosensory, and wound-healing processes, which are potential to control and prevent DED pathogenesis and the vicious circle. Therefore, this study was carried out to determine whether CBR ligand eye drops can provide a multiple-target therapy for DED. The project hereby consisted of three parts, addressing consecutive objectives: Firstly, this study confirms the involvement of CBRs (in particular, CB1R and CB2R) in DED pathomechanism based on an experimental DED mouse model (desiccating stress model). CB1R and CB2R were detected by RT-qPCR and in-situ hybridization techniques in the cornea, conjunctiva, and lacrimal glands. During DED-induction, CB1R and CB2R expressions were increasing, concurrent with significant DED phenotypes (low tear production, high score of cornea epitheliopathy, and reduced cornea sensitivity). Furthermore, different CBRs ligands were topically applied to DED-induced mice. CBRs therapy suppressed the increasing trend of CBR expression, which coincided with improved phenotype readouts. Tetrahydrocannabinol (THC) is a promising candidate for anti-inflammatory effects, together with protecting nerve morphology and maintaining corneal sensitivity. Secondly, an in-vitro wound-healing model was developed to characterize the influence of CBR on the re-epithelialization process. Interestingly, while CB1R was found to have a significant effect, selective CB2R ligand did not influence the re-epithelialization. In detail, activating CB1R improved the wound-healing rate while selectively inhibiting CB1R delayed the wound-healing process. Furthermore, tetrahydrocannabinol (THC), a non-selective agonist, showed a biphasic effect: high concentration (from 1 to 10 µM) delayed wound healing, while low concentration (from 0.01 to 0.5 µM) increased the rate. This finding supports the functional role of CBRs in DED pathogenesis and management. Thirdly, we proposed two eyedrop formulations for THC, in which THC was formulated in the form of micelle in water at the nanoscale (around 10nm). All ingredients are already used in pharmaceuticals and bio-products, so the formulations are expected to be safe and well-tolerated. Additionally, the formulation steps are feasible with low technical complexity, showing promise for commercial scaling-up. The finally proposed formulation contains 0.5% THC, adequate to provide a significant effect, as shown in the in-vivo model in the first part. Also, the obtained results confirmed stability when stored at room temperature or refrigerator (4-8oC), facilitating its use by patients. In summary, this study confirmed the potentiality of CBR and CBR ligands, notably THC, as a multiple-target therapy for dry eye patients

Rigorous derivation of Michaelis-Menten kinetics in the presence of diffusion

Reactions with enzymes are critical in biochemistry, where the enzymes act as catalysis in the process. One of the most used mechanisms for modeling enzyme-catalyzed reactions is the Michaelis-Menten (MM) kinetic. In the ODE level, i.e. concentrations are only on time-dependent, this kinetic can be rigorously derived from mass action law using quasi-steady-state approximation. This issue in the PDE setting, for instance when molecular diffusion is taken into account, is considerably more challenging and only formal derivations have been established. In this paper, we prove this derivation rigorously and obtain MM kinetic in the presence of spatial diffusion. In particular, we show that, in general, the reduced problem is a cross-diffusion-reaction system. Our proof is based on improved duality method, heat regularisation and a suitable modified energy function. To the best of our knowledge, this work provides the first rigorous derivation of MM kinetic from mass action kinetic in the PDE setting.Comment: Comments are welcome

Effect of land-use changes resulting from shrimp farming on acid sulfate soils in the Can Gio coastal wetland area (Vietnam)

Acid sulfate soils in coastal wetland areas are particularly vulnerable to land-use changes. We identifid the potential impacts of land-use changes in the Can Gio coastal wetland area in Vietnam due to the reclamation of acid sulfate soils from shrimp farms. Our study applied the support of vector machine algorithm in ENVI software to observe land-use changes from 1995 to 2015, using Landsat Thematic Mapper and Operational Land Imager data. We classifid the land use of the study area into four major classes including vegetation, bare land, dedicated land and aquaculture land. Our study successfully met the overall classifiation accuracy requirement above 95% and kappa statistics above 0.95. Between 1995 and 2006, about 2,938.05 ha of bare land and 1,464.66 ha of vegetation (mangrove forest) were converted to aquaculture land. In contrast, between 2006 and 2015, 2,423.88 ha of aquaculture land converted back to bare land, mainly related to the abandonment of shrimp ponds due to crop failure and disease. The disturbance of acid sulfate soils through initial soil reclamation and subsequent fallowing is considered a key reason for hastening and extending soil acidifiation in the study area. We collected 144 topsoil samples from 17 fallowed ponds in two batches, and 142 of these were acidic: 128 samples were extremely and strongly acidic (pH < 5.5), 14 samples were moderately and slightly acid (pH between 5.5 and 6.5), and only two samples were neutral (pH over 6.5)

Toward a fast and accurate modeling strategy for thermal management in air-cooled data centers

Computational fluid dynamics (CFD) has become a popular tool compared to experimental measurement for thermal management in data centers. However, it is very time-consuming and resource-intensive when used to model large-scale data centers, and may not be ready for real-time thermal monitoring. In this thesis, the two main goals are first to develop rapid flow simulation to reduce the computing time while maintaining good accuracy, and second, to develop a whole building energy simulation (BES) strategy for data center modeling. To achieve this end, hybrid modeling and model training methodologies are investigated for rapid flow simulation, and a multi-zone model is proposed for BES. In the scope of hybrid modeling, two methods are proposed, i.e., the hybrid zero/two-equation turbulence model utilizing the zone partitioning technique and a combination of turbulence and floor tile models for the development of the composite performance index. It shows that the zero-equation coupled with either body force and modified body force tile models have the best potential in reducing the computing time, while preserving reasonable accuracy. The hybrid zero/two-equation method cuts down the computing time in half compared to the traditional practice of using only two-equation model. In the scope of model training, reduced order method via proper orthogonal decomposition (POD) and response surface methodology (RSM) are comprehensively studied for data center modeling. Both methods can quickly reconstruct the data center thermal profile and retain good accuracy. The RSM method especially shows numerous advantages in several optimization studies of data centers. Whether it is for the tile selection to control the server rack temperature difference or impacting the decision for the input design parameters in the early stage of data center infrastructure design, RSM can replace the costly experiments and the time-consuming and resource-intensive CFD simulations. Finally, for the whole BES study, the proposed multi-zone model is found to be much more effective compared to the common use single zone model. The location factor plays an important role in deciding whether some of boundary conditions are affecting the cooling electricity consumption. In addition, the effect of supply temperature and volumetric flow rate have significant effects on the energy consumption

Confinement Effects on Non-Reactive and Reactive Transport Processes: Insights from Molecular Dynamics Simulations

Exploring the thermodynamic, structural and transport properties, coupled with the reactivity of complex geo-fluids in porous systems is vital in geochemistry, and it also has repercussions in a variety of fields, most importantly the manufacturing of chemicals in the industry. Experimental and computational studies can shed light on the behaviour of fluids in confinement, thereby providing insights for industrial applications in various areas such as catalysis, gas recovery, separations, and adsorption. This thesis seeks to obtain some fundamental understanding of the behaviour of fluids confined in narrow pores as well as the role of pores in reactive-transport processes by implementing the atomistic molecular dynamics (MD) simulation techniques. In collaboration with experimentalists, validation has been achieved for selected systems. The systems were simulated as confined within a realistic cylindrical pore of diameter ~16 Å carved out of amorphous silica. A series of MD simulations implementing classical force fields were conducted to examine the effect of bulk pressure and water loading on the mobility of propane confined within cylindrical silica pores. The transport properties of propane were found to depend on pressure, as well as on the amount of water present. At high H2O loading, propane transport is hindered by “molecular bridges” formed by water molecules. The results are in quantitative agreement with neutron scattering data conducted for propane-water systems confined in MCM-41–type materials. To investigate the effect of narrow pores on the possible abiotic synthesis of methane in sub-surface conditions, MD simulations implementing the reactive force field (ReaxFF) formalism were performed. Although the ReaxFF force fields were successfully parameterized to describe dynamics of complex reactive chemical systems, the simulation results reveal that they can also be able to reliably predict bulk properties of nonreactive pure fluids (CH4, CO2, H2O, and H2). However, the agreement with both simulations implementing classical force fields and experiments depends strongly on fluids and thermodynamics conditions considered. When ReaxFF molecular dynamics simulations were conducted for CO2 in the presence of excess H2 within the amorphous silica nanopores, no CH4 was obtained at the conditions considered; however, CO was found to be a stable product, suggesting that the silica pore surface facilitates the partial reduction of CO2 to CO. Because the results could be important for CCUS applications, we investigated the wetting properties of calcite in the presence of water and CO2, at various pressures and salt content. Comparison with experiments suggests that much fundamental research is still needed to design safe and reliable geological storage repositories

Structural Driving Factors for the Coupled Electron and Proton Transfer Reactions in Mitochondrial Cytochrome BC1 Complex: Binding Geometries of Substrates and Protonation States of Ionizable Amino Acid Side Chains Near Qi and Qo Sites

Coupled electron and proton transfer (CEPT) events are fundamental for many bioenergetic conversions that involve redox reactions. Understanding the details underlying CEPT processes will advance our knowledge of (1) how nature regulates energy conversion; (2) our strategies for achieving renewable energy sources; (3) how to cope with CEPT dysfunction diseases. Studies of the detailed mechanism(s) of CEPT in biological systems is challenging due to their complex nature. Consequently, controversies between the concerted and sequential mechanism of CEPT for many systems remain. This dissertation focuses on the bovine mitochondrial cytochrome bc1 complex. CEPT in the bc1 complex operates by a modified Q-cycle (1) and catalyzes electron transfer from ubiquinol (QH2), to cyt c via an iron sulfur cluster (ISC) and to the low potential hemes of cyt b, where it reduces ubiquinone (UQ). The electron transfer is coupled to the translocation of protons across the mitochondrial inner membrane, generating a proton gradient that drives ATP synthesis. Although the Q-cycle is widely accepted as the model that best describes how electrons and protons flow in bc1, detailed binding geometries at the Qo site (QH2 oxidation site) and Qi site (UQ reduction site) remain controversial. The binding geometries play critical roles in the thermodynamic and/or kinetic control of the reaction and protonatable amino acid side chains can participate in the proton transfer. The central focuses of this dissertation are molecular dynamics simulations of cofactor binding geometries near the Qo and Qi sites, calculations of the pKa values of ionizable amino acid side chains implicated in cofactor binding, especially the ISC-coordinated histidines, and implications for the proposed mechanism(s) of CEPT. For the first time, pKa values of the ISC-coordinated histidines are differentiated. The computed pKa values of 7.8±0.5 for His141 and 9.1±0.6 for His161 agree well with experiment (7.63±0.15 and 9.16±0.28). Thus, His161 should be protonated at physiological pH and cannot be the first proton acceptor in the QH2 oxidation. Water mediated hydrogen bonds between substrate models and the protein and water accessibility to the Qo and Qi sites were maintained in simulations, implying that water molecules are likely the proton donors and acceptors