Search Results (35)

Background: Tofacitinib is mainly used in the adult population for immune-mediated inflammatory diseases. There is little information available on the pharmacokinetics of tofacitinib in pediatric patients, populations with hepatic impairment and renal impairment, and patients with drug–drug interactions (DDIs). This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of tofacitinib in the populations mentioned above. Methods: We developed the PBPK models in PK-Sim^® and evaluated the models with observed clinical PK data. The Monte Carlo algorithm was used for parameter identification. Results: The adult PBPK model accurately simulated the pharmacokinetic profiles of all administration scenarios. The geometric mean fold errors for the predicted/observed maximum concentration and area under the curve are 1.17 and 1.16, respectively. The extrapolated models accurately simulated the pharmacokinetic characteristics of tofacitinib. The pediatric patients aged 12-to-<18 years and 2-to-<6 years need to adjust the dose to 4 mg BID and 1.7 mg BID, respectively, to achieve comparable steady-state exposures to 5 mg BID in adults. The populations with moderate hepatic impairment and severe renal impairment need to reduce the dose to 50% and 75% of the original dose, respectively. Tofacitinib should be reduced to 50% and 65% of the original dose for concomitant use with fluconazole and ketoconazole, respectively, and increased to 150% of the original dose for concomitant use with rifampicin. Conclusions: We developed a tofacitinib PBPK model and extrapolated it to special populations and DDIs. The predictive results of the models can help the rational use of tofacitinib in these populations. Full article

This paper introduces a mean profit- conditional value-at-risk (CVaR) model for purchasing electricity on the day-ahead market (DA) by electric vehicles fleet aggregator (EVA). EVA controls electric vehicles (EVs) during their workplace parking, enabling smart charging and cost savings by accessing market prices that are potentially lower than flat rates available during home charging. The proposed stochastic linear programming model leverages market price scenarios to optimize aggregated charging schedules, which serve as templates for constructing effective DA bidding curves. It integrates an aspiration/reservation-based formulation of the mean profit-risk criteria, specifically Conditional Value at Risk (CVaR) to address the EVA’s risk aversion. By incorporating interactive analysis, the framework ensures adaptive and robust charging schedules and bids tailored to the aggregator’s risk preferences. Its ability to balance profitability with risk is validated in case studies. This approach provides a practical and computationally efficient tool for EV aggregators of global companies that can benefit from the workplace charging their fleets thanks to buying energy in the DA market. Full article

Amidst the global energy crisis in 2022, the Spanish and Portuguese governments introduced a subsidy to natural gas (“the Iberian exception”), attempting to lower the wholesale electricity market prices, with the understanding that gas-fired-combined cycle gas turbines (CCGTs) are price-setting technologies most of the time, directly or indirectly. The subsidy succeeded in lowering the market price but induced several other effects, such as (1) the increase in cleared energy in the Spanish market (mostly produced with gas), (2) the bias in the import/export cross-border position between Spain and France (Spain became a net exporter to France immediately), or (3) the consequent increase in congestion rents, which serve to lightly finance the subsidy, among other effects. This paper provides a framework for clustering the different effects based on the market participation phases: the subsidy, the market bidding, the market results, and surplus and rents. Moreover, this paper builds on the theoretical market models, with and without subsidies, and with and without cross-border exchanges. Based on the real market bids, the subsidies, and the generators’ data, we reconstruct the supply and demand curves and simulate the counterfactual market scenarios in order to illustrate and quantify the effects. We highlight the quantification of the theoretical effect of the transfer of rents, from non-fossil to fossil fuel producers, induced by the gas subsidy. Full article

We aimed to evaluate the effectiveness of an intensive care unit (ICU) round checklist, FAST HUGS BID (Feeding, Analgesia, Sedation, Thromboembolic prophylaxis, Head-of-bed elevation, Ulcer prophylaxis, Glycemic control, Spontaneous breathing trial, Bowel regimen, Indwelling catheter removal, and De-escalation of antibiotics—abbreviated as FD hereafter), in improving clinical outcomes in patients with severe trauma. We included patients admitted to our trauma ICU from 2016 to 2020 and divided them into two groups: before (before-FD, 2016–2017) and after (after-FD, 2019–2020) implementation of the checklist. We compared patient characteristics and clinical outcomes, including ICU and hospital length of stay (LOS) and in-hospital mortality. Survival analysis was performed using Kaplan–Meier curves and multivariable logistic regression models; furthermore, multiple linear regression analysis was used to identify independent factors associated with ICU and hospital LOS. Compared with the before-FD group, the after-FD group had significantly lower in-hospital mortality and complication rates, shorter ICU and hospital LOS, and reduced duration of mechanical ventilation. Moreover, implementation of the checklist was a significant independent factor in reducing ICU and hospital LOS and in-hospital mortality. Implementation of the FD checklist is associated with decreased ICU and hospital LOS and in-hospital mortality. Full article

Climate change (CC) impacts on hydrology pose significant global concerns due to their effects on water availability, thereby impacting various human activities reliant on this essential resource. This study assesses the influence of CC on the water supply in the Angostura-Bolivia basin. We employed the RegCM4 system, which develops its own regional climate models (RCMs) tailored to the Angostura basin using specific convective schemes, diverging from reliance on pre-existing RCMs, like those provided by CORDEX. Methodologically, the study involves hydrometeorological data collection and analysis, utilizing dynamic and statistical downscaling methods to refine the RCMs derived from ERA-Interim reanalysis data. Subsequently, precipitation and temperature projections are generated under CC scenarios (RCP 4.5 and RCP 8.5) for both near (2045–2055) and far (2065–2075) future periods, compared to the historical period (1981–2010). The final stage employs the HydroBID system to project future runoff, considering both perturbed and unperturbed hydrometeorological data under CC effects. The analysis of flow duration curves for 50%, 75%, and 90% exceedance probabilities reveals a significant reduction in flows across all scenarios, indicating a noteworthy impact on water availability. These findings underscore the urgency of comprehending and adapting to CC on hydrology, emphasizing the critical importance of sustainable water resource management amidst evolving climatic conditions. Full article

The increased uptake of variable renewable energy sources has increased electricity price volatility in many energy pool markets, providing an opportunity for storage systems to profit through energy arbitrage. Comparison between the cost or value of storage systems engaging in energy arbitrage should be performed on a levelised basis due to differences in system lifetime. Existing energy arbitrage models with bid/offer curves and imperfect forecasting are typically computationally expensive and are impractical for calculating lifetime levelised cost metrics. In this work, an open-source modular energy arbitrage model with bid and offer curve inputs was developed for a lithium-ion battery energy storage system (BESS) and pumped hydro system (PHS) to analyse lifetime levelised cost and revenue. The mixed integer linear program scheduling module included a new piece-wise linearised description of PHS charging behaviour for rapid optimisation. A one-at-a-time sensitivity analysis indicated that levelised cost and revenue were highly sensitive to discharging efficiency. In a case study based on Australia’s National Electricity Market, imperfect forecasting with no risk hedging was found to increase levelised costs by up to 24% and decrease levelised revenue by up to 50% relative to perfect price forecasting, despite 95% of prices being forecast to be within $35/MWh of the actual trading price. BESS levelised costs were more significantly correlated with consistent low risk bids (Kendall Tau-b of 0.75), since the undiscounted capital costs contribute to a larger proportion of the overall costs than in the PHS systems. Full article

China’s electricity market reform has posed a real challenge to the large-scale hydropower system. Taking the world’s largest watershed hydropower system, the Three Gorges large hydropower system (TGLHS), as the engineering background, this study analyzes the issues and strategies of dispatching and trading in the electricity market. The analysis indicates that the TGLHS exhibits unique difficulties because of transprovincial and transregional power transmission. Major issues including the multi-dimensional and multi-time-scale nested allocation of hydropower energy, the bidding and performance of cascaded hydropower plants in multiple electricity markets, as well as multiple uncertainties in the runoff; electricity prices in multiple markets are also elaborated upon. The corresponding suggested strategies are proposed to cope with the aforementioned issues: (1) for multi-dimensional and multi-scale nested allocation problems, it is necessary to comprehensively consider monthly market transactions and priority generation plans, and establish a profit maximization model; (2) propose a bidding decision-making linkage and segmented bidding optimization model for cascades upstream and downstream hydropower stations; (3) construct a model for decomposing the annual and monthly planned electricity consumption curves and developing operational plans for giant cascade power stations that are suitable for cross-provincial and cross-regional power transmission and transformation; (4) a runoff, electricity price, and market distribution model has been proposed, laying the foundation for further research on multi-scale optimization models for hydropower. Finally, prospects for research on the participation of large-scale hydropower systems in the electricity market are summarized, expecting to promote the marketization of large cascaded hydropower systems. The dispatching and trading of the TGLHS implies that it is important and necessary to explore market theories and methods considering hydropower characteristics and operation needs. Full article

This study presents an architectural framework for the blockchain-based usage-based insurance (UBI) policy auction mechanism in the internet of vehicles (IoV) applications. The main objective of this study is to analyze and design the specific blockchain architecture and management considerations for the UBI environment. An auction mechanism is developed for the UBI blockchain platform to enhance consumer trust. The study identifies correlations between driving behaviors and associated risks to determine a driver’s score. A decentralized bidding algorithm is proposed and implemented on a blockchain platform using elliptic curve cryptography and first-price sealed-bid auctions. Additionally, the model incorporates intelligent contract functionality to prevent unauthorized modifications and ensure that insurance prices align with the prevailing market value. An experimental study evaluates the system’s efficacy by expanding the participant pool in the bidding process to identify the winning bidder and is investigated under scenarios where varying numbers of insurance companies submit bids. The experimental results demonstrate that as the number of insurance companies increases exponentially, the temporal overhead incurred by the system exhibits only marginal growth. Moreover, the allocation of bids is accomplished within a significantly abbreviated timeframe. These findings provide evidence that supports the efficiency of the proposed algorithm. Full article

Miltefosine-Allopurinol (MIL-AL) combination is reported to be one of the most effective treatments for canine leishmaniosis, thanks to its oral administration and MIL-documented low impact on renal function. However, MIL-AL is considered a second-choice treatment when compared to meglumine-antimoniate—allopurinol combination, mainly due to the risk of earlier relapses. The aim of this study was to evaluate the efficacy of the MIL-AL protocol during a long-term follow-up with an average duration of nine years. Dogs were living in Southern Italy (Puglia, Italy) in an area considered endemic for Canine leishmaniosis (CanL). Inclusion criteria were clinical and/or clinicopathological signs consistent with CanL; positive result to Leishmania quantitative ELISA; and negativity to the most frequent canine vector-borne infections. All dogs received 2 mg/kg MIL for 28 days, and 10 mg/kg AL, BID, for a period varying between 2 and 12 months. Ancillary treatments were allowed according to the clinical condition of the dog. A total clinical score and a total clinicopathological score were calculated at each time point by attributing one point to each sign or alteration present and then by adding all points. Improvement after each treatment was defined by the reduction of at least 50% of the total score. A survival analysis (Kaplan–Meier curve) was performed for quantifying the probability of the events occurring during the study follow-up. The following events were considered: decreased and negative ELISA results; improvement/recovery of the clinical and clinicopathological alterations; and relapse of leishmaniasis. One hundred seventy-three dogs (75f and 98m) were retrospectively included in the study by examining their clinical records since the first diagnosis of CanL. One hundred forty-three (83%) dogs were under five years of age. The mean duration of the follow-up period was 5.4 (±1.1) years with a minimum of 3.2 years and a maximum of 9 years. All dogs received a first treatment of MIL-AL at inclusion; then, during the follow-up course, 30 dogs required a second treatment, 2 dogs required a third treatment and 1 dog required a fourth and a fifth treatment. The mean time interval between the first and the second treatment was 27.2 (±18.3) months. After the first treatment, all dogs had decreased ELISA levels, in an average interval of 2.6 (±1.6) months. One hundred seventy dogs (98%) experienced a clinical improvement (mean time 3.0 ± 4.9 months); 152 (88%) dogs were considered clinically recovered after a mean time of 16.7 ± 13.5 months. A similar trend was observed for clinicopathological alterations; interestingly, proteinuria decreased in most dogs (p < 0.0001—Chi-square for trends). Thirty dogs experienced relapses, the earliest after 4.8 months. The mean time without relapse was 90.4 (±2.5) months. In relapsed dogs, the mean time for clinical improvement after the second treatment was 8.6 (±12.6) months, whereas it was 11.0 (±15.4) months for clinicopathological alterations. Five dogs had limited gastrointestinal side effects associated with MIL treatment. The present study confirms that the MIL-AL protocol can be considered one of the most effective treatments for CanL therapy, mainly for its capacity to provide a long-time clinical improvement in a large majority of treated dogs. As reported in the literature, the clinical stabilization of dogs does not occur immediately after treatment, probably due to the particular pharmacokinetic properties of MIL. The efficacy of MIL-AL decreases in dogs that need more than one treatment, suggesting the necessity to alternate anti-Leishmania drugs for the treatment of relapses. Side effects were transient and slight, even in dogs that required several treatments. Full article

Linezolid is used off-label for treatment of central nervous system infections. However, its pharmacokinetics and target attainment in cranial cerebrospinal fluid (CSF) in tuberculous meningitis patients is unknown. This study aimed to predict linezolid cranial CSF concentrations and assess attainment of pharmacodynamic (PD) thresholds (AUC:MIC of >119) in plasma and cranial CSF of adults and children with tuberculous meningitis. A physiologically based pharmacokinetic (PBPK) model was developed to predict linezolid cranial CSF profiles based on reported plasma concentrations. Simulated steady-state PK curves in plasma and cranial CSF after linezolid doses of 300 mg BID, 600 mg BID, and 1200 mg QD in adults resulted in geometric mean AUC:MIC ratios in plasma of 118, 281, and 262 and mean cranial CSF AUC:MIC ratios of 74, 181, and 166, respectively. In children using ~10 mg/kg BID linezolid, AUC:MIC values at steady-state in plasma and cranial CSF were 202 and 135, respectively. Our model predicts that 1200 mg per day in adults, either 600 mg BID or 1200 mg QD, results in reasonable (87%) target attainment in cranial CSF. Target attainment in our simulated paediatric population was moderate (56% in cranial CSF). Our PBPK model can support linezolid dose optimization efforts by simulating target attainment close to the site of TBM disease. Full article

The expression level of the tumor suppressor p53 is controlled by the E3 ubiquitin ligase MDM2 with a regulatory feedback loop, which allows p53 to upregulate its inhibitor MDM2. In this manuscript we demonstrated that p90RSK binds and phosphorylates MDM2 on serine 166 both in vitro and in vivo by kinase assay, immunoblot, and co-immunoprecipitation assay; this phosphorylation increases the stability of MDM2 which in turn binds p53, ubiquitinating it and promoting its degradation by proteasome. A pharmacological inhibitor of p90RSK, BI-D1870, decreases MDM2 phosphorylation, and restores p53 function, which in turn transcriptionally increases the expression of cell cycle inhibitor p21 and of pro-apoptotic protein Bax and downregulates the anti-apoptotic protein Bcl-2, causing a block of cell proliferation, measured by a BrdU assay and growth curve, and promoting apoptosis, measured by a TUNEL assay. Finally, an immunohistochemistry evaluation of primary thyroid tumors, in which p90RSK is very active, confirms MDM2 stabilization mediated by p90RSK phosphorylation. Full article

The installed capacity of PVs in the distribution grid is affected not only by network constraints, but also by the economic viability of the related investments. Depending on the market participation models, this is determined critically by the Day Ahead Market (DAM) prices. Increasing RES installations in a country usually results in a long term drop in the market prices and, as a consequence, a reduction in the income of the PVs investors and possible market cannibalization. This paper models the effect of large-scale penetration of PVs on the market prices and identifies the optimal penetration level for the viability of PV projects. The optimal penetration is highly related to the installation of new PVs and this is a parameter for the analysis. Therefore, the paper identifies different penetration costs for the different installation cost. Furthermore, the PV network hosing capacity can be increased by distribution network reinforcements. Therefore, in the paper, the investments for enhancement of the distribution grid are assessed with respect to market prices and are analyzed at the macroscopic level. Again, the analysis considers different costs for network reinforcements. Full article

Background: Triple fixed-dose combination (FDC) therapy is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations and/or symptoms not controlled by dual FDCs. Since no randomized controlled trials (RCTs) have directly compared the different inhaled corticosteroid/long-acting β₂-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) FDCs, we performed a meta-analysis to compare the impact of the current available ICS/LABA/LAMA FDCs in COPD. Methods: A meta-analysis was performed by connecting beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide or glycopyrrolate (BDP/FOR/GLY), budesonide (BUD)/GLY/FOR, and fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) FDCs via ICS/LABA or LABA/LAMA FDCs arms. The safety and efficacy profiles were investigated, and the Implemented Bidimensional Surface under the cumulative ranking curve analysis (IBiS) was carried out. Protocol registration: CRD42022301189. Results: Data from 21,809 COPD patients were extracted from the ETHOS, IMPACT, KRONOS, and TRILOGY studies. No significant (p > 0.05) differences were detected across the triple FDCs with respect to the risk of exacerbation, trough forced expiratory volume in the first second (FEV₁), transition dyspnea index (TDI), St. George’s Respiratory Questionnaire (SGRQ), risk of serious adverse events (SAEs), cardiovascular (CV) SAEs, pneumonia, and all-cause mortality. According to IBiS score, BDP/FOR/GLY 200/12/25 µg twice daily (BID) was the FDC reporting the best combined efficacy/safety profile (area 41.41%), although FF/UMEC/VI 100/62.5/25 µg once daily (QD) showed the greatest efficacy profile (50.54%). The protection against mortality related to the dose of ICS. Conclusions: All triple FDCs are effective and safe in COPD regardless of the regimen of administration (twice daily vs. once daily), with no relevant difference in the risk of CV SAEs and pneumonia. Full article

Electricity price forecasting has been a booming field over the years, with many methods and techniques being applied with different degrees of success. It is of great interest to the industry sector, becoming a must-have tool for risk management. Most methods forecast the electricity price itself; this paper gives a new perspective to the field by trying to forecast the dynamics behind the electricity price: the supply and demand curves originating from the auction. Given the complexity of the data involved which include many block bids/offers per hour, we propose a technique for market curve modeling and forecasting that incorporates multiple seasonal effects and known market variables, such as wind generation or load. It is shown that this model outperforms the benchmarked ones and increases the performance of ensemble models, highlighting the importance of the use of market bids in electricity price forecasting. Full article

Background: Thyroid cancer is the most common endocrine malignancy. Most PTC patients have a good prognosis; however, there are 5–20% of PTC patients with extra-thyroidal invasion, vascular invasion, or distant metastasis who have relatively poor prognoses. The aim of this study is to find new and feasible molecular pathological markers and therapeutic targets for early identification and appropriate management. Methods: The GEO and TCGA databases were used to gather gene expression data and clinical outcomes. Based on gene expression and clinical parameters, we developed a ferroptosis-related gene-based prognostic model and a nomogram. CCK-8, wound-healing, and transwell assays were conducted to explore the proliferation, migration, and invasion abilities of thyroid cancer cells. Results: We found 75 genes associated with ferroptosis that were differentially expressed between normal thyroid tissue and thyroid cancer tissues. The prognostic values of the 75 ferroptosis-related gene expressions were evaluated using the TCGA-THCA dataset, and five (AKR1C3, BID, FBXW7, GPX4, and MAP3K5) of them were of significance. Following that, we chose AKR1C3 as the subject for further investigation. By combining gene expression and clinical parameters, we developed a ferroptosis-related gene-based prognostic model with an area under the curve (AUC) of 0.816, and the nomogram also achieved good predictive efficacy for the three-year survival rate of thyroid cancer patients. Knocking down AKR1C3 enhances thyroid cancer cell proliferation, invasion, and migration abilities. Conclusions: A ferroptosis-related gene-based prognostic model was constructed that provided unique insights into THCA prognosis prediction. In addition, AKR1C3 was found to be a progression promoter in thyroid cancer cell lines. Full article