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ABSTRACTIntroductionSodium−glucose cotransporter (SGLT) 2 inhibitors reduce glucose reabsorption in the kidney, increase glucosuria, and improve glycemia. Besides glycemic efficacy, the class also lowers risk of cardiovascular and renal disease.Areas coveredThe authors describe late phase trials of empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin. Safety and efficacy endpoints in monotherapy, combination therapy, cardiovascular, and renal outcomes trials have been identified and presented.Expert opinionSGLT2 inhibitors appear to be safe and effective agents that improve glycemia when used alone or in combination with any other approved antihyperglycemic medications. Other beneficial effects include reductions in body weight and blood pressure, improvements in renal outcomes, all-cause mortality, cardiovascular mortality, and worsening heart failure.

The interaction of surface-active drugs with surfactants, used in the simulation of artificial membranes by direct and reversed micelles, mainly determines the transport of drugs in the body and the complex process of the binding to receptors. Besides, the delivery of drugs into the body via microemulsions has been successfully used to reduce the first-pass metabolism. The structure of mixed reverse microemulsions based on the ionic surfactant sodium bis(2-ethylhexyl)sulfosuccinate (AOT) and the cationic surface active drug promethazine hydrochloride (PMT) was studied spectroscopically in the infrared and UV-visible regions, as well as using electrical conductivity and dynamic light scattering. The release profile of PMT from AOT-based microemulsions was studied using cellulose dialysis bags. The introduction of PMT additive into the water pockets of reverse AOT micelles leads to: a) an increase in free water fraction and a decrease in bound water fraction; b) changing the chromatographic retention factors of the model compounds; c) insignificant influence on the values of the binding constant of optical probe o-nitroaniline with the head groups of AOT; d) quenching of water-induced percolation in electrical conductance of reverse AOT microemulsions; e) a slight decrease in the size of water droplets at the same values of the molar ratio of water/surfactant. The release of PMT from the aqueous system obeys Fick’s law of diffusion (n = 0.4852), and the release of PMT from microemulsions is based on non-Fickian or anomalous diffusion.

Solar photovoltaic devices are a clean/sustainable energy resource used to generate electricity in the current era. Overall, the energy yielded from these devices is used to supply the electrical loads in order to meet energy needs. Any building can store electricity produced by renewable energy technology supplies through energy storage using a battery system. This study aims to determine the system's optimal performance characteristics within solar photovoltaic (PV) systems, including coupling the solar system/inverter and controller/battery storage (BS). This study builds a model using solar simulation in the ‘system advisor model’ programme, utilising a photovoltaic system with the integration of battery storage, which can improve energy efficiency. High-efficiency battery storage is needed for optimum performance and high reliability. To do so, an integrated model was created, including solar photovoltaics systems and battery storage. Energy storage (ES) is a challenge that must be carefully considered when investigating all energy system technologies. The results indicated that the overall system has an annual energy yield of approximately 1353 kWh/kW and a performance ratio of 0,85. The high energy yield occurred during the summer, owing to more sunshine hours and the high magnitude of solar intensity. The ultimate finding proposes an optimisation framework to estimate/delineate the energy of generation/storage arrangement based on the power potential.

ABSTRACTIntroductionBromocriptine mesylate quick release (QR) is a dopamine D2 receptor agonist and is the only oral, primarily centrally acting drug that can be used for the treatment of adults with type 2 diabetes.Areas coveredThe authors describe current recommendations on the use of bromocriptine mesylate QR. Major efficacy and safety parameters of the late phase trials, including The Cycloset Safety Trial, have been identified and presented.Expert opinionEfficacy of bromocriptine mesylate QR monotherapy appears to be low but is compensated by favorable safety profile: low risk of hypoglycemia and no weight gain. The latter makes the drug an acceptable choice for obese individuals with type 2 diabetes. As a valuable additional benefit, bromocriptine is associated with significant cardiovascular risk reduction. Current recommendations include bromocriptine mesylate QR as part of dual or triple antihyperglycemic therapy especially in individuals with type 2 diabetes who are hesitant to add injectable treatment options and/or have cardiovascular disease.

BackgroundThe travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe.MethodsA cross-sectional analysis including 518 treatment-nai¨ve patients with retinoblastoma residing in 40 European countries and 1024 treatment-nai¨ve patients with retinoblastoma residing in 43 African countries.ResultsCapture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI −12.4 to −5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease.ConclusionsFewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with potential cardiovascular involvement. The aim of this study was to assess left ventricular (LV) systolic function in a large cohort of patients with SLE using standard echocardiographic measurements and global longitudinal strain (GLS) by two-dimensional speckle-tracking analysis. Furthermore, the association between echocardiographic parameters and the occurrence of cardiovascular events was assessed.

IMPORTANCE: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child’s life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. OBJECTIVES: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. MAIN OUTCOMES AND MEASURES: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. RESULTS: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle–income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle–income countries vs upper-middle–income countries and HICs, 5.74 [95% CI, 4.30-7.68]). CONCLUSIONS AND RELEVANCE: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

The microenvironment of water droplets of nonionic polyoxyethylene (4) lauryl ether reverse micelles was investigated with infrared and ultraviolet-visible spectroscopy, also by viscosity and dynamic light scattering measurements in the presence of biological surfactant sodium cholate as additive. Influence of concentrations of polyoxyethylene (4) lauryl ether and sodium cholate on the microstructure of mixed reverse micelles was studied. Influence of sodium cholate as additive on the ratio of free, bound and trapped water fractions was studied via deconvolution of the O-H stretching vibrational absorption spectra in the region of 3 000–3 800 cm−1into three subpeaks with a Monte Carlo method. Several characteristic parameters of reverse microemulsions were calculated on the basis of measurements of their kinematic viscosity. A different influence of concentration of sodium cholate on the binding constant and association degree of optical probes (o-nitroaniline and methyl orange respectively) to ethylene oxide groups of nonionic surfactant was observed. It was found that the bound water fraction, the binding constants and association degrees, the relative density of water pockets, etc. change their values passing through an extremum under the influence of sodium cholate.

Application of additional oxygen for managing acute exacerbation of Chronic Obstructive Pulmonary Disease (COPD) has an associated risk of oxygen toxicity. The aim of this work is to determine the appropriate level of oxygen for managing such conditions using a mathematical model. In this approach, a noted respiratory regulation model is modified to simulate COPD condition. Using the proposed model, it is established that higher inspired oxygen increases alveolar oxygen, as well as alveolar carbon dioxide. It is also shown that higher inspired oxygen increases oxygen saturation and lowers the ventilation-perfusion ratio mismatch. Using quadratic combination of alveolar oxygen and carbon dioxide pressure, an objective function is proposed to calculate the optimal level of inspired oxygen. Results obtained from this analysis methodology are in agreement with clinical data.

ABSTRACTIntroduction: Alpha-glucosidase inhibitors (AGIs) – oral antihyperglycemic drugs, inhibit upper gastrointestinal enzymes that break down complex carbohydrates into glucose. As a result, the absorption of glucose is delayed, postprandial glucose reduced, and glycemic control improved.Areas covered: In this review, the authors describe the current recommendations on the use of the three major approved AGIs (acarbose, miglitol, voglibose). Efficacy and safety parameters together with ethnic considerations have been highlighted throughout the manuscript. The article also discusses potential diabetes prevention and cardiovascular effects of these medications.Expert opinion: The overall safety and efficacy of this class of drug appears to be high: AGIs do not increase the risk of hypoglycemia, do not cause weight gain; they also significantly improve postprandial hyperglycemia, have been associated with the reduction in risk factors for cardiovascular disease and may also delay the progression of prediabetes to T2DM. In general, we continue to believe that acarbose, miglitol, and voglibose should be used as third-line add on treatment options to other anti-hyperglycemic agents. However, this class can have earlier consideration in elderly and/or when metformin is contraindicated.

The epoxy compositions with ionic liquids (ILs) differing in the alkyl chain length of imidazolium cation (butyl or decyl), anion type [N(CN)2¯, BF4¯, Cl¯], as well as ILs concentration (1, 3, and 9 phr) have been prepared, and their curing characteristics at ambient and elevated temperatures have been investigated. Rheometric, differential scanning calorimetry, and Fourier transform infrared measurements revealed substantial differences in the curing characteristics dependent mainly on the IL anion type and its concentration. TGA results showed that thermal decomposition of IL influenced the onset temperature of epoxy resins cross-linking reactions during heat treatment. Dynamic mechanical thermal analysis measurements showed that the type of IL anion had an effect on Tgand tan δ values as well. For materials cross-linked with ILs containing dicyanamide anion the highest Tg(ca. 170 °C) and the lowest tan δ (0.26) values have been found. On the basis of the obtained results and literature data the mechanism of epoxy resin cross-linking in the presence of imidazolium ionic liquids has been proposed.

ABSTRACTIntroduction: Oral antidiabetic medications are important in many type 2 diabetes care plansAreas covered: The article summarizes the cardiovascular and renal safety data for DPP-4 inhibitors and SGLT-2 inhibitors and specific safety data particular to each class.Expert opinion: DPP-4 and SGLT-2 inhibitors provide unique anti-hyperglycemic mechanisms. The cardiovascular safety profiles of DPP-4 inhibitors are promising, but do not show the strong CV risk reduction of empagliflozin and canagliflozin. The heart failure signal associated with DPP-4 inhibitor use is unclear with differing agents, demonstrating increased risk or maybe even protective effects. The risk reduction in cardiovascular disease associated with SGLT-2 inhibitors has translated to recommendations to consider these therapies early in the treatment pathway. Both classes have potential safety concerns that necessitate appropriate patient selection and thorough education on potential side-effects. DPP-4 inhibitors are considered to have neutral or in some studies beneficial renoprotective effects. SGLT-2 inhibitor safety effects on the kidney are more complex. There are reports of acute kidney injury occurring soon after initiating SGLT-2 inhibitor therapy. However, there are large recent studies that have demonstrated the beneficial effect of SGLT-2 inhibitors in slowing the progression of established chronic kidney disease.Trial registration:ClinicalTrials.gov identifier: NCT01243424.Trial registration:ClinicalTrials.gov identifier: NCT01897532.Trial registration:ClinicalTrials.gov identifier: NCT02065791.Trial registration:ClinicalTrials.gov identifier: NCT01986881.

•J-VCharacterisation of the three component sub-cells of a triple-junction cell as a function of different AM.•Prediction of cell temperature by an iteration technique that converges to find a steady operating temperature.•Increases in air mass have a significant effect on thermal and electrical performance.

To our knowledge, the characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate, with a cross-sectional study, the prevalence of disease categories, treatment methods, and disease status in patients from across different geographical areas and from countries with diverse wealth status.

•A complex numerical modelling technique has been established to accurately predict the cell temperature and thermal load on a High Concentration Multi-Junction Photovoltaic Cell.•It has been established that a heat transfer coefficient of at least 2.4 kW/m2K is required to keep a multi-junction cell below a safe operating temperature of 80 °C, for a concentration ratio of 1000x.•The optimum mesh selection is performed for accuracy model simulation.

ABSTRACTIntroduction: Glucagon-like peptide-1 (GLP-1) receptor agonists are highly potent antihyperglycemic drugs that impose low risk of hypoglycemia and also result in body weight reduction. Currently, all approved members of the class require administration by injection.Areas covered: This manuscript reviews oral semaglutide—an experimental GLP-1 receptor agonist in phase-3 clinical development. Available pharmacological and clinical data of the drug are reviewed, and important end-points described.Expert opinion: Oral peptide delivery has become possible with the discovery of absorption enhancers. The clinical development program of once-daily oral semaglutide has shown superiority in reducing glycosylated hemoglobin and body weight in comparison with placebo and active comparators (sitagliptin, liraglutide, and empagliflozin). Safety and tolerability of oral semaglutide is in line with injectable members of the class. Delayed gastric emptying, local increase in pH, and enhanced absorption do not seem to affect the exposure of a number of other oral drugs that have been tested (metformin, digoxin, oral contraceptive ethinylestradiol/levonorgestrel, lisinopril, warfarin, furosemide and rosuvastatin). Clinical questions for further investigation include the effectiveness and safety of oral semaglutide in cardiovascular indications.

ABSTRACTIntroduction: Drug-induced hepatic injury is the most common cause of acute liver failure in the United States. Peroxisome proliferator-activated receptor alpha (PPARα)-mediated drugs are included among the approximately 900 natural and synthetic substances, which have shown hepatotoxicity.Areas covered: This review will focus on fibrates – PPARα agonists and their implication in causing liver injury.Expert opinion: Compelling evidence for fibrate-induced hepatotoxicity is not available. Results have been varying because several large randomized clinical trials have reported similar elevations of plasma transaminase levels in fibrate or placebo treated groups. On the other hand, one meta-analysis has reported an increased risk of hepatotoxicity when fibrates are combined with statins. Fibrate induced clinically apparent liver damage has been demonstrated in case reports. However, there is a wide spectrum of clinical phenotypic presentations of these cases (onset of injury, pattern of enzyme elevation and resolution of the symptoms), which reduces the ability to identify specific cause and effect of any putative fibrate-induced hepatotoxicity. Thus, the current recommendations for using fibrates include monitoring of aminotransferase levels especially if combined with statins and discontinuation of the treatment only if the levels persist above three times the upper limit of normal.

ABSTRACTIntroduction: It is critical for individuals with type 2 diabetes mellitus (T2DM) to maintain optimal glycemia while avoiding hypoglycemia, control body weight, and reduce cardiovascular risk. The GLP-1 receptor agonists stimulate glucose-dependent insulin release (low risk of hypoglycemia), inhibit glucagon secretion, slow gastric emptying and suppress appetite (weight loss). The new members of the class are available as once daily or weekly injections. Additionally, some members of the class have demonstrated reduced cardiovascular risk.Areas covered: This manuscript describes semaglutide – a new investigational long acting GLP-1 receptor agonist. The key trials from the clinical development process are reviewed and important end-points highlighted.Expert opinion: Once-weekly semaglutide has shown superiority in reducing glycosylated hemoglobin and body weight in comparison with placebo and active comparators when used as monotherapy or in combination treatment. In addition, semaglutide improved markers of β-cell function and have shown cardiovascular risk reduction similar to once daily liraglutide. Although, overall semaglutide safety was comparable to other GLP-1 receptor agonists (low risk of hypoglycemia and high frequency of gastrointestinal side effects), increase in retinopathy complications requires further investigation.

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ABSTRACTIntroduction: Normal pregnancy development involves gradual decline in insulin sensitivity, which sometimes requires pharmacotherapy. Insulin is the drug of choice for gestational and pregestational diabetes. Metabolism of traditional insulins results in inadequate onset and duration of action and marked peak activity. These properties increase risk of excessive glucose excursions, which are especially undesirable during pregnancy. Insulin analogs have been emerging as a safer and more effective treatment of diabetes during pregnancy.Areas covered: This manuscript reviews currently used antihyperglycemic agents: fast and long-acting insulins, metformin and glyburide. Trials demonstrating their efficacy and safety during pregnancy are described. Certain drug metabolism considerations (e.g. affinity to IGF-1) are emphasized.Expert opinion: The theories that insulin analogs bind to immunoglobulin and cross placenta have been disproved. Lispro, aspart, glargine and detemir do not transfer across the placenta and do not result in adverse maternal and neonatal outcomes. In addition, favorable pharmacokinetic profiles (rapid onset and 24-hour near peakless activity) substantially reduce blood glucose variability including hypoglycemia. We believe that insulin analogs should be given strong consideration for the treatment of diabetes during pregnancy. Metformin has also proven to be safe and may be considered as an initial single agent for milder gestational diabetes.

ABSTRACTIntroduction:This manuscript describes 21 drug targets in the area of diabetes and related conditions that were discontinued in 2015.Areas covered:The material for this paper was obtained by contacting biopharmaceutical companies, reviewing their pipelines, press releases and annual reports. Additionally, the authors searched clinicaltrials.gov, PubMed and general Internet search engines. Majority of the compounds were in early stages of the development.Expert opinion:Business reasons for termination of the drug projects emerge more and more frequently over the years. Safety signals usually appear early in the development and are often associated with novel drugs. 2015 medicines with inadequate efficacy were unable to compete with existing approved members of the class they represented.

AimsTo study the possible association of catechol-O-methyltransferase (COMT)Val158Met polymorphism with multiple and solitary uterine leiomyomas (ULs) and to check whether the COMTVal/Val genotype is associated with MED12exon 2 mutations in fibroids.MethodsThe COMTVal158Met allele and genotype frequencies were compared between age-matched women with ULs (n=104) and controls (n=59). Patients with UL were subcategorised by diagnosis of solitary (n=59) or multiple (n=45) fibroids and by the presence of somatic MED12exon 2 mutations in at least one fibroid (n=32) or in neither fibroid (n=26). The association of COMTVal/Val genotype with the presence of any ULs, solitary/multiple ULs and ULs positive/negative for MED12exon 2 mutations was evaluated by χ2tests using a dominant genotype model (G/G vs G/A+A/A) and expressed as ORs and 95% CIs.ResultsThe COMTVal/Val genotype frequency did not differ between the patients with UL and the controls (28.8% vs 18.6%, p=0.149, OR 1.77; CI 0.81 to 3.86). However, it was significantly higher in the patients who had multiple UL compared with the solitary UL (40% vs 20.3%, p=0.028, OR 2.61; CI 1.09 to 6.24) and to the controls (40% vs 18.6%, p=0.016, OR 2.91; CI 1.20 to 7.06). No association of the COMTVal/Val genotype with UL-specific MED12exon 2 mutations was found (p=0.662, OR 0.77; CI 0.23 to 2.53).ConclusionsWomen with COMTVal/Val genotype are at high risk of developing multiple uterine fibroids either positive or negative for MED12exon 2 mutations. These data are important to design new strategies for UL prophylaxis and treatment.

Introduction:Speckle tracking echocardiography (STE) can be an useful tool for detecting early and subtle myocardial changes in patients with systemic lupus erythematosus (SLE)Hypothesis:The present study aimed to perform systemic review and meta-analysis of the studies based on the assessment of the left ventricular (LV) systolic function with LV ejection fraction (LVEF) and LV global longitudinal strain (LV GLS).Methods:Data were analysed according to an established protocol of the Cochrane Collaboration steps and meta-analysisResults:A total of 850 papers were collected, of those 10 papers including 174 442 SLE patients and 45 608 723 controls with heart failure, also 20 papers including 1121 SLE patients and 1010 controls with measured LVEF and 9 papers including 462 patients and 356 controls with measured LV GLS were selected. Studies have shown, that patients with SLE were characterized with higher prevalence of heart failure as compared to controls (Fig1). Patients with SLE exhibited lower levels of LVEF as compared to controls too (Fig.1), some included studies have shown that the difference in terms of LVEF between groups is not always significant. LV GLS was more deteriorated in SLE patients as compared to controls (Fig.2a, 2b), moreover some studies showed significant association between deteriorated LV GLS and cardiovascular events.Conclusions:Patients with SLE are characterized with high prevalence of heart failure. LV systolic function as measured by LVEF and LV GLS is significantly more affected in SLE patients. Data suggest that LV GLS may improve risk-stratification in patients with SLE.

One degree of freedom (DOF) tele-hydraulic manipulation using force reflecting bilateral control will be investigated. The primary objective in the development of a simple one DOF experimental rig was to allow the investigation of different tele-control strategies prior to their implementation on the eight DOF tele-hydraulic excavator system. Because of the friction nonlinearity characteristic in hydraulic system, high steady state error and overshoot have occurred in the position response as a typical imperfect implementation of associated control dynamic. In this situation, there is a necessity to be able to effectively utilizing the intelligent friction compensated controller. This fuzzy compensator combined with fuzzy controller will be implemented to enhance the maneuverability performance. Experiments were carried out and the experimental results illustrated that the above compensated intelligent framework can improve the bilateral performance

Introduction:Type 2 diabetes is the fastest growing non-communicable chronic disease worldwide. One of the newer treatment options is the class of sodium–glucose cotransporter 2 inhibitors that offer improved glycemia through increased urinary glucose excretion. The class has shown to be effective, safe and well-tolerated in newly diagnosed and long-standing diabetes. Additional benefits of the inhibitors include low risk of hypoglycemia and weight loss.Areas covered:This perspective reviews ipragliflozin– a sodium–glucose cotransporter 2 inhibitor – that has gained approval for clinical use in Type 2 diabetes in Japan. The paper discusses pharmacokinetics (PK), pharmacodynamics, clinical efficacy, safety and tolerability of the drug.Expert opinion:Due to its efficacy (hemoglobin A1c reduction of 1%), safety (low risk of hypoglycemia and very low rate of urinary tract infections), favorable PK interaction with other anti-diabetes medications and mechanism of action that is independent from β-cell function and insulin sensitivity, ipragliflozin can be used as a monotherapy or as an add-on to other agents in any stage of Type 2 diabetes.