Unilaterally removing implicit subsidies for maritime fuels

Many academics and policymakers agree that implicit tax subsidies for maritime fuels — which are currently granted around the world — are inefficient, but that their abolishment requires a unanimous international agreement. Such an agreement is deemed indispensable because any unilateral action would be impossible due to massive tax competition in this industry, competitiveness effects and the legal limits on regulating an industry operating mostly in international waters, thus outside of any state’s jurisdiction. However, an international agreement to solve these problems has proven impossible to reach, thus resulting in the conservation of the status quo. To break this dead

How Much Carbon Pricing is in Countries' Own Interests? The Critical Role of Co-Benefits

This paper calculates, for the top twenty emitting countries, how much pricing of carbon dioxide (CO2) emissions is in their own national interests due to domestic co-benefits. On average, nationally efficient prices are substantial, $57.5 per ton of CO2 (for year 2010), reflecting primarily health co-benefits from reduced air pollution at coal plants and, in some cases, reductions in automobile externalities (net of fuel taxes/subsidies). Pricing co-benefits reduces CO2 emissions from the top twenty emitters by 13.5 percent. However, co-benefits vary dramatically across countries (e.g., with population exposure to pollution) and differentiated pricing of CO2 emissions therefore yields higher net benefits (by 23 percent) than uniform pricing

Does Glucose Variability Influence the Relationship Between Mean Plasma Glucose and HbA1cHbA_{1c} Levels in Type 1 and Type 2 Diabetic Patients?

Objective: The A1C-Derived Average Glucose (ADAG) study demonstrated a linear relationship between $HbA_{1c}$ and mean plasma glucose (MPG). As glucose variability (GV) may contribute to glycation, we examined the association of several glucose variability indices and the MPG-$HbA_{1c}$ relationship. Research Design and Methods: Analyses included 268 patients with type 1 diabetes and 159 with type 2 diabetes. MPG during 3 months was calculated from 7-point self-monitored plasma glucose and continuous glucose monitoring. We calculated three different measures of GV and used a multiple-step regression model to determine the contribution of the respective GV measures to the MPG-$HbA_{1c}$ relationship. Results: GV, as reflected by SD and continuous overlapping net glycemic action, had a significant effect on the MPG-$HbA_{1c}$ relationship in type 1 diabetic patients so that high GV led to a higher $HbA_{1c}$ level for the same MPG. In type 1 diabetes, the impact of confounding and effect modification of a low versus high SD at an MPG level of 160 mg/dL on the $HbA_{1c}$ level is 7.02 vs. 7.43 and 6.96 vs. 7.41. All GV measures showed the same tendency. Conclusions: In only type 1 diabetic patients, GV shows a significant interaction with MPG in the association with $HbA_{1c}$. This effect is more pronounced at higher $HbA_{1c}$ levels. However, the impact of GV on the $HbA_{1c}$ level in type 1 diabetes is modest, particularly when $HbA_{1c}$ is close to the treatment target of 7%

Label-Free Time-Resolved Monitoring of Photolipid Bilayer Isomerization by Plasmonic Sensing

The photo-isomerization of the photolipid azo-PC, a derivative of phosphatidylcholine containing an azobenzene group in its sn2 acyl chain, enables optical control over key properties of supported lipid bilayers (SLBs), such as membrane fluidity and bilayer thickness. However, azobenzenes are well-known for their interaction with various dyes through photo-modulation and -sensitization pathways, presenting a challenge in bilayer characterization by fluorescence microscopy. Label-free tools capable of monitoring the switching process of photolipid SLBs at the nanoscale are therefore highly desired. In this study, the use of dark field scattering spectroscopy on gold nanorods as a highly sensitive approach is demonstrated for analyzing the reversible photo-isomerization dynamics of photolipid SLBs in real time at the single particle level

An Evidence-Based Rationale for Dose De-escalation of Subcutaneous Atezolizumab

Background: Atezolizumab is a programmed death-ligand 1 (PD-L1) checkpoint inhibitor for the treatment of different forms of cancer. The subcutaneous formulation of atezolizumab has recently received approval. However, treatment with atezolizumab continues to be expensive, and the number of patients needing treatment with this drug continues to increase. Objective: We propose two alternative dosing regimens for subcutaneous atezolizumab to reduce drug expenses while ensuring effective exposure; one may be directly implemented in the clinic. Patients and Methods: We developed two alternative dose interval prolongation strategies based on pharmacokinetic modeling and simulation. The first dosing regimen was based on patients’ weight while maintaining equivalent systemic drug exposure by adhering to Food and Drug Administration (FDA) guidelines for in silico dose adjustments. The second dosing regimen aimed to have a minimum atezolizumab concentration above the 6 µg/mL threshold, associated with 95% intratumoral PD-L1 receptor saturation for at least 95% of all patients. Results: We found that, for the weight-based dosing regimen, the approved 3-week dosing interval could be extended to 5 weeks for patients &lt; 50 kg and 4 weeks for patients weighing 50–65 kg. Besides improving patient convenience, these alternative dosing intervals led to a predicted 7% and 12% cost reduction for either the USA or European population. For the second dosing regimen, we predicted that a 6-week dosing interval would result in 95% of the patients above the 6 µg/mL threshold while reducing costs by 50%. Conclusions: We have developed and evaluated two alternative dosing regimens that resulted in a cost reduction. Our weight-based dosing regimen can be directly implemented and complies with FDA guidelines for alternative dosing regimens of PD-L1 inhibitors. For the more progressive alternative dosing regimen aimed at the intratumoral PD-L1 receptor threshold, further evidence on efficacy and safety is needed before implementation.</p

Model-Informed Development of a Cost-Saving Dosing Regimen for Sacituzumab Govitecan

Background: The antibody–drug conjugate sacituzumab govitecan is approved for metastatic triple-negative breast cancer and has shown promising results in various other types of cancer. Its costs may limit patient access to this novel effective treatment modality. Objective: The purpose of this study was to develop an evidence-based rational dosing regimen that results in targeted drug exposure within the therapeutic range while minimizing financial toxicity, to improve treatment access. Patients and Methods: Exposure equivalent dosing strategies were developed based on pharmacokinetic modeling and simulation by using the published pharmacokinetic model developed by the license holder. The alternative dose was based on the principle of using complete vials to prevent spillage and on the established non-linear relationship between body weight and systemic exposure. Equivalent exposure compared to the approved dosing regimen of 10 mg/kg was aimed for. Equivalent exposure was conservatively defined as calculated geometric mean ratios within the 0.9–1.11 boundaries for area under the concentration–time curve (AUC), trough concentration (Ctrough) and maximum concentration (Cmax) of the alternative dosing regimen compared to the approved dosing regimen. Since different vial sizes are available for the European Union (EU) and United States (US) market, because body weight distributions differ between these populations, we performed our analysis for both scenarios. Results: Dosing regimens of sacituzumab govitecan for the EU (&lt; 50 kg: 400 mg, 50–80 kg: 600 mg, and &gt; 80 kg: 800 mg) and US population (&lt; 40 kg: 360 mg, 40–65 kg: 540 mg, 65–90 kg: 720 mg, and &gt; 90 kg: 900 mg) were developed, based on weight bands. The geometric mean ratios for all pharmacokinetic outcomes were within the predefined equivalence boundaries, while the quantity of drug used was 21.5% and 19.0% lower for the EU and US scenarios, respectively. Conclusions: With the alternative dosing proposal, an approximately 20% reduction in drug expenses for sacituzumab govitecan can be realized while maintaining an equivalent and more evenly distributed exposure throughout the body weight range, without notable increases in pharmacokinetic variability.</p

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer

Background: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. Objective: We aimed to develop alternative dosing regimens to reduce drug expenses. Methods: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. Results: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. Conclusions: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.</p

Three critical hydrogen bonds determine the catalytic activity of the Diels–Alderase ribozyme

Compared to protein enzymes, our knowledge about how RNA accelerates chemical reactions is rather limited. The crystal structures of a ribozyme that catalyzes Diels–Alder reactions suggest a rich tertiary architecture responsible for catalysis. In this study, we systematically probe the relevance of crystallographically observed ground-state interactions for catalytic function using atomic mutagenesis in combination with various analytical techniques. The largest energetic contribution apparently arises from the precise shape complementarity between transition state and catalytic pocket: A single point mutant that folds correctly into the tertiary structure but lacks one H-bond that normally stabilizes the pocket is completely inactive. In the rate-limiting chemical step, the dienophile is furthermore activated by two weak H-bonds that contribute ∼7–8 kJ/mol to transition state stabilization, as indicated by the 25-fold slower reaction rates of deletion mutants. These H-bonds are also responsible for the tight binding of the Diels–Alder product by the ribozyme that causes product inhibition. For high catalytic activity, the ribozyme requires a fine-tuned balance between rigidity and flexibility that is determined by the combined action of one inter-strand H-bond and one magnesium ion. A sharp 360° turn reminiscent of the T-loop motif observed in tRNA is found to be important for catalytic function

Prevalence of avian influenza A(H5) and A(H9) in live bird markets in Bangladesh

We conducted a cross-sectional study in live bird markets (LBMs) in Dhaka and Chittagong, Bangladesh, to estimate the prevalence of avian influenza A(H5) and A(H9) viruses in different types of poultry and environmental areas by using Bayesian hierarchical logistic regression models. We detected these viruses in nearly all LBMs. Prevalence of A(H5) virus was higher in waterfowl than in chickens, whereas prevalence of A(H9) virus was higher in chickens than in waterfowl and, among chicken types, in industrial broilers than in cross-breeds and indigenous breeds. LBMs with >1 wholesaler were more frequently contaminated by A(H5) virus than retail-only LBMs. Prevalence of A(H9) virus in poultry and level of environmental contamination were also higher in LBMs with >1 wholesaler. We found a high level of circulation of both avian influenza viruses in surveyed LBMs. Prevalence was influenced by type of poultry, environmental site, and trading patterns because our study included previously collected data

Transitions to food democracy through multilevel governance

status: publishe