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Background: Based on the legal framework laid down in section 130b (9) of Book V of the German Social Code, various criteria are relevant for the negotiated price for new patented drugs in Germany. European reference prices (ERPs) are one criterion. The ERP is based on the ex-factory prices (EFPs) of the countries included in the European country basket. However, in some of these countries, the EFP is not published due to confidential wholesale margins. Wholesale margins must therefore be estimated and deducted from purchase prices. In this context literature-based estimates to date do not assume regressive margins with higher pharmaceutical prices. This assumption is questionable and can lead to systematically underestimated country prices, especially for high-priced drugs. Percentage wholesale margins in the majority of European countries develop to a comparable extent regressively with increasing prices. It should therefore be examined (1) whether statistical models can predict the margins of individual countries, in principle and especially for countries where margins are unknown and regressive trends are likely, and (2) to what extent the estimation of margins improves when regressive statistical models are used to estimate margins instead of cross-price averages published in the literature. Methods: Qualitative preliminary research explores the basic wholesale pricing mechanisms in countries with confidential wholesale margins. Wholesale margins for reimbursable drugs were then modeled for regulated European countries. Estimation quality and impact of the model was compared to estimations based on average margins. Results: In both regulated countries and in countries with confidential wholesale margins, percentage margins of wholesalers develop regressively as drug prices rise. Regressive courses of margins can be resiliently modeled for the regulated countries using a power distribution with significantly lower mean squared errors in a linear mixed model in comparison to literature-based estimations with country-specific cross-price averages. Conclusion: If there is reason to believe that margins are regressive, confidential wholesale margins are expected to be better estimated by the power function based on margins of regulated countries than by the published country-specific average margins, reducing significantly inaccurate effects on margin estimations of high-price drugs. [ABSTRACT FROM AUTHOR]

Der Gesetzgeber hat mit dem 2019 eingeführten Instrument der anwendungsbegleitenden Datenerhebung (AbD) die Möglichkeit geschaffen, vergleichende Daten in der laufenden Versorgung zu erheben. Die AbD dient der Generierung von Evidenz und dem Zweck der Nutzenbewertung nach dem AMNOG (Arzneimittelmarktneuordnungsgesetz) als Grundlage erneuter Erstattungsbetragsverhandlungen. Ein zentraler Punkt für die Realisierbarkeit einer AbD sind die derzeitigen Anforderungen an den Nachweis eines quantifizierbaren Zusatznutzens. In einer Simulationsstudie wurden die derzeit im Methodenpapier des IQWiG geforderten rigiden Effektschwellen, aber auch modifizierte Anforderungen untersucht. Eingeflossen sind alle abgeschlossenen Orphan-Drug-Verfahren seit Einführung der frühen Nutzenbewertung im Jahr 2011. Die Studie zeigt, dass das derzeit vom IQWiG vorgeschlagene Vorgehen für die AbD verhältnismäßig große Patientenzahlen erfordert, die vor allem bei Orphan Drugs häufig kaum zu erreichen sind. Anhand der simulierten, veränderten Kriterien wird ein alternatives Vorgehen vorgeschlagen, das der besonderen Situation einer AbD als adjustiertem, jedoch nicht-randomisiertem Vergleich gerecht werden könnte.

With the flourishing development of global economy, effective management of production supply chains is crucial for the competitiveness of enterprises. Optimizing supply chain networks can not only improve the efficiency of resource allocation but also enhance market responsiveness and systemic risk resistance. Traditional supply chain network optimization methods, focusing mostly on linear models and static analysis, fall short in addressing the growing complexity and dynamism. The emergence of Graph Neural Network (GNN) models in recent years has offered new opportunities to tackle non-linearity and structural dynamism in supply chain networks. However, existing research still faces methodological limitations in supply chain node relationship mining and benefit assessment. This study introduces an optimization and benefit assessment method for production supply chain networks based on GNNs. Firstly, by developing a node role type-aware graph neural network model, this paper achieves in-depth mining and optimization of node relationships within production supply chain networks. Secondly, a hierarchical factor analysis method is used to comprehensively assess the benefits of the production supply chain. This method can dynamically capture changes in node roles and relationships within the supply chain network, optimize the network structure, and provides a multidimensional, multilevel framework for benefit assessment. This study not only expands the application of GNN in the field of supply chain management but also provides a new analytical tool for the comprehensive assessment of supply chain benefits.

Copyright of Revista Iberoamericana de Ciencia, Tecnologia y Sociedad is the property of Centro de Estudios sobre Ciencia, Desarrollo y Educacion Superior and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

For newly authorised medicinal products with new active substances, a benefit assessment is carried out at the time of their market access in Germany. The subject of this assessment is the question of the additional benefit of the new active substance compared to the current standard therapy (the “appropriate comparator”) with regard to patient-relevant outcomes. Orphan drugs (medicinal products for rare diseases) are treated separately. For these, the additional benefit is considered proven with market access, regardless of the actual data. Only with annual sales of at least 30 million euros a regular assessment will be conducted. In this case, data for comparison with an appropriate comparator has to be submitted. An analysis shows that in such regular benefit assessments, an additional benefit cannot be proven for orphan drugs in more than half of the cases. In 2019, in recognition of the often insufficient evidence base for orphan drugs, the „Anwendungsbegleitende Datenerhebung“ (AbD: collection of routine practice data) was established as a further component of the benefit assessment. Accordingly, the Federal Joint Committee (G-BA) can demand an AbD for orphan drugs as well as for medicinal products with a conditional marketing authorisation or marketing authorisation under exceptional circumstances. The pharmaceutical company is responsible for conducting the AbD. The AbD has to generate data on the new active substance as well as meaningful data for comparison with the appropriate comparator. The AbD is to be conducted as a study without randomisation, and the G-BA has to determine concrete specifications on the methodology and patient-relevant endpoints.The first step of the AbD is the preparation of a study protocol (SP) and a statistical analysis plan (SAP) under the responsibility of the company. These documents are checked with regard to their content-related and methodological suitability for conducting the AbD including the associated evaluation of the data. The adjustment for confounders represents a central methodological aspect of an AbD. The SPs and SAPs submitted so far had significant deficits in this regard. There is a substantial need for development in this area.

In this paper, firstly, the load monitoring characteristics of new energy power consumption are studied and analyzed in terms of both steady-state and transient characteristics, and suitable characteristic values are selected for different types as the basis of load decomposition. A comparative analysis of various types of load imprints is conducted to highlight the advantages of steady-state harmonic features as load monitoring feature data. Then, an evaluation model of the demand response potential of electricity information collection is established based on a multi-objective optimization algorithm, and technical and economic analysis of electricity information collection is carried out to evaluate the response potential of power companies collecting customer data. Finally, the situation and benefits of collecting electricity consumption information for new energy power are analyzed. The daily maximum load moments of typical users are all cut by more than 10%, the peak load portion cut by more than 97% is also more obvious, and the maximum moments of valley filling response are all more than 11%. D Power saved a total of 3.759 billion yuan in labor costs by reducing labor costs by 400 million yuan after adopting electricity consumption information collection. The indices of excellent and qualified management benefit and social benefit evaluation of electricity consumption information collection are above 0.8. Overall, the benefits of electricity consumption information collection for new energy power with basic steady-state harmonic characteristics are significant and effective.

Zur Beurteilung der Wirksamkeit und Sicherheit eines neuen Wirkstoffes ist für die europäische Zulassungsbehörde (European Medicines Agency, EMA) die randomisierte kontrollierte Studie (RCT) der Goldstandard. Mit der Einführung des AMNOG (Arzneimittelmarktneuordnungsgesetz) am 01.01.2011 rückten methodische Aspekte zur geeigneten Beantwortung der relevanten Fragestellung, nämlich der Nutzenbewertung innovativer Pharmakotherapien gemäß § 35a SGB V, in den Vordergrund. Im Grundsatz wird für die Evaluation der relativen Wirksamkeit eines neuen Arzneimittels gegenüber der zweckmäßigen Vergleichstherapie (zVT) klinische Evidenz aus RCT als Bewertungsgrundlage herangezogen. Für Arzneimittel zur Therapie seltener Erkrankungen (Orphan Drugs, OD) bringt die Evidenzgenerierung mittels RCT besondere Herausforderungen mit sich. Aufgrund dessen traten für Orphan Drugs im Jahr 2000 die EU-gemeinschaftsrechtlichen Besonderheiten in Kraft mit dem Ziel, die Erforschung, Entwicklung und das Inverkehrbringen geeigneter Arzneimittel durch die pharmazeutische Industrie zu fördern (Verordnung (EG) Nr. 141/2000). Vor demselben Hintergrund gelten auch im AMNOG-Verfahren für Orphan Drugs besondere Regelungen, die die Ziele der europäischen Verordnung auf nationaler Ebene implementieren (§ 35a Abs. 1 S. 11 f. SGB V.). So gilt der Zusatznutzen von Orphan Drugs mit der Zulassung als belegt. Am 23.12.2021 veröffentlichte das Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) das Arbeitspapier GA21-01, im Rahmen dessen es sich kritisch mit dem Evidenzkörper und der Nutzenbewertung von Orphan Drugs auseinandersetzt (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) 2021). In dem Arbeitspapier nimmt das IQWiG einen Vergleich vor zwischen einer Nutzenbewertung der Orphan Drugs, die die Besonderheiten bei Markteintritt berücksichtigt (im Folgenden OD-Nutzenbewertung), und einer regulären Nutzenbewertung. Das IQWiG schlussfolgert aus seiner Analyse im Arbeitspapier GA21-01, dass auch für Orphan Drugs ausschließlich randomisiert kontrollierte Studien mit Vergleich gegenüber der zweckmäßigen Vergleichstherapie als Evidenzbasis für die Bewertung des Zusatznutzens berücksichtigt werden sollten.

Abstract Background Vestibular schwannomas are benign tumours for which various treatments are available. We performed a systematic review of prospective controlled trials comparing the patient-relevant benefits and harms of single-fraction stereotactic radiosurgery (sfSRS) with microsurgical resection (MR) in patients with vestibular schwannoma. Methods We searched for randomized controlled trials (RCTs) and non-randomized prospective controlled trials in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and study registries (last search: 09/2021) and also screened reference lists of relevant systematic reviews. Manufacturers were asked to provide unpublished data. Eligible studies investigated at least one patient-relevant outcome. We assessed the risk of bias (high or low) at the study and outcome level. If feasible, meta-analyses were performed. We graded the results into different categories (hint, indication, or proof of greater benefit or harm). Results We identified three non-randomized prospective controlled trials of generally low quality with evaluable data on 339 patients with unilateral vestibular schwannoma. There was an indication of greater benefit of sfSRS compared with MR for facial palsy (OR 0.06, 95% CI 0.02–0.21, p < 0.001, 2 studies), hearing function (no pooled estimate available, 2 studies), and length of hospital stay (no pooled estimate available, 2 studies). We found no clinically relevant differences for mortality, vertigo, headaches, tinnitus, balance function, work disability, adverse events, and health-related quality of life. Conclusions Our systematic review indicates that sfSRS has greater benefits than MR in patients with unilateral vestibular schwannoma. However, it is unclear whether this conclusion still holds after 2 years, as long-term studies are lacking. It is also unclear whether the effects of sfSRS are similar in patients with bilateral vestibular schwannomas. Long-term prospective studies including patients with this condition would therefore be useful. Systematic review registration The full (German language) protocol and report (Commission No. N20-03) are available on the institute’s website: www.iqwig.de/en/projects/n20-03.html

Precision medicine is increasingly important in cancer treatment. Tumor-agnostic therapies are used regardless of tumor entity because they target specific biomarkers in tumors. In Germany, the benefit assessment of oncological pharmaceuticals has traditionally been entity specific. Thus, the assessment of tumor-agnostic therapies leaves stakeholders with various challenges. Our aim was to systematically identify challenges and possible solutions for the benefit assessment of therapies in tumor-agnostic indications using a 2-step sequential qualitative approach. To identify relevant challenges, we conducted qualitative interviews with different stakeholders who were involved in previous benefit assessments of tumor-agnostic therapies in Germany. To identify possible solutions for these challenges, we systematically searched MEDLINE, Embase, and the websites of European health technology assessment bodies for relevant literature. We identified 9 categories of challenges of which the following were deemed particularly relevant: the absence of direct comparative studies, challenges regarding the use of basket studies and indirect comparisons, challenges in determining the appropriate comparative therapy in a tumor-agnostic indication, and challenges on the system side. Seven categories of solutions were identified, including an increased use of real-world evidence, making conditional decisions in the context of systematic reassessments, splitting the field of application, and finding (new) ways to design and analyze basket studies. A range of possible solutions, which can help to meet the identified challenges in Germany, have been found. Future research should investigate the acceptance and feasibility of these solutions. • The benefit assessment of tumor-agnostic therapies leaves stakeholders with various challenges. • The article systemized these challenges and identified possible solutions for the benefit assessment of tumor-agnostic therapies in Germany. Categories of challenges included the determination of the appropriate comparator, no comparative studies, and basket studies. Solutions proposed in the literature are manifold and include, for example, the increased use of real-world evidence. • We identified a range of possible solutions, which could guide future reforms, in Germany and beyond, toward more value in health. Future research should investigate the acceptance and feasibility of these solutions. [ABSTRACT FROM AUTHOR]

Industry and scientists develop new nanomaterials and nano-enabled products to make use of the specific properties that the nanoscale can bring. However, the benefit of a nano-enabled product over a conventional product is not always a given. This paper describes our development of a Benefit Assessment Matrix (BAM) that focuses on the functional, health and environmental benefits of nanomaterials, nano-enabled manufacturing and nano-enabled products. The BAM is an Excel spreadsheet-based tool to help researchers and small and medium-sized enterprises assess these potential benefits throughout their product's life cycle while they are still in the early phase of the innovation process. Benefit indicators were developed based on a review of the literature on the life cycles and intrinsic properties of nanomaterials, nano-enabled manufacturing and nano-enabled products. Assessing the benefits of a nano-enabled product involves a comparative approach, contrasting them against the benefits of a conventional reference product. To help users understand the reliability of the benefits, the BAM identifies the evidence of the benefit claimed. The BAM provides a different action plan for each phase of the stage–gate product innovation process. The tool's applications and potential are presented using three case studies, focusing at different phases of the innovation process: nano-clays used in internal automobile body-panels, nano-TiO2 used in outdoor facade coatings and nano-Ag used in T-shirts. Using these cases studied, we highlight how the results from the BAM can be used to give recommendations for moving towards the concept of safe and sustainable by design in nanotechnology development. [ABSTRACT FROM AUTHOR]

Background: Vestibular schwannomas are benign tumours for which various treatments are available. We performed a systematic review of prospective controlled trials comparing the patient-relevant benefits and harms of single-fraction stereotactic radiosurgery (sfSRS) with microsurgical resection (MR) in patients with vestibular schwannoma. Methods: We searched for randomized controlled trials (RCTs) and non-randomized prospective controlled trials in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and study registries (last search: 09/2021) and also screened reference lists of relevant systematic reviews. Manufacturers were asked to provide unpublished data. Eligible studies investigated at least one patient-relevant outcome. We assessed the risk of bias (high or low) at the study and outcome level. If feasible, meta-analyses were performed. We graded the results into different categories (hint, indication, or proof of greater benefit or harm). Results: We identified three non-randomized prospective controlled trials of generally low quality with evaluable data on 339 patients with unilateral vestibular schwannoma. There was an indication of greater benefit of sfSRS compared with MR for facial palsy (OR 0.06, 95% CI 0.02–0.21, p < 0.001, 2 studies), hearing function (no pooled estimate available, 2 studies), and length of hospital stay (no pooled estimate available, 2 studies). We found no clinically relevant differences for mortality, vertigo, headaches, tinnitus, balance function, work disability, adverse events, and health-related quality of life. Conclusions: Our systematic review indicates that sfSRS has greater benefits than MR in patients with unilateral vestibular schwannoma. However, it is unclear whether this conclusion still holds after 2 years, as long-term studies are lacking. It is also unclear whether the effects of sfSRS are similar in patients with bilateral vestibular schwannomas. Long-term prospective studies including patients with this condition would therefore be useful. Systematic review registration: The full (German language) protocol and report (Commission No. N20-03) are available on the institute's website: www.iqwig.de/en/projects/n20-03.html [ABSTRACT FROM AUTHOR]

Is there such a thing as a "best scientific methodology" in regulatory (decision-oriented) science? By examining cases from varying regulatory processes, we argue that there is no best scientific method for generating decision-relevant data. In addition, in regulatory science, the most suitable methodologies often differ from what is considered best practice in knowledge-oriented (academic) science. In data generation for regulatory purposes, we are faced with a wide spectrum of preferred methodologies as well as controversy as to methodological choice. What goes by the most adequate scientific method can and will—justifiably and rationally—vary significantly according to context and use. In order to make this argument, we analyze four case studies, two from risk assessment and two from benefit assessment. Our analysis shows that it is the noncognitive objectives of a particular regulatory process that determine what counts as the most appropriate scientific method. We use the concept of bounded rationality to indicate that those methodological choices, despite being context-dependent, can be interpreted as rational. [ABSTRACT FROM AUTHOR]

Project portfolio benefits (PPBs) are typically regarded as a key feature for successful project portfolios in practice. However, there is little prescriptive knowledge that offers guidance on how to tackle the realisation and improvement of PPBs. To narrow this research gap, we develop a systematic assessment model to analyse and optimize PPBs. Innovatively considering the recessive benefits resulting from synergies among different project components, four subsystems of PPBs are identified. Subsequently, by synthesizing the interrelations within and between subsystems, a system dynamics model is developed to assess PPBs dynamically. Then, a numerical example is adopted to validate the applicability and effectiveness of the proposed model. It can be concluded that the model is exploitable in academia and practice. For academia, this study expands benefit management tools and provides a theoretical basis for project portfolio benefit optimization. For practitioners, the straightforward model and procedure contribute to enhancing the management of PPBs. [ABSTRACT FROM AUTHOR]

The metallurgy industry consumes a considerable amount of coal and fossil fuels, and its carbon dioxide emissions are increasing every year. Replacing coal with renewable, carbon-neutral biomass for metallurgical production is of great significance in reducing global carbon consumption. This study describes the current state of research in biomass metallurgy in recent years and analyzes the concept and scientific principles of biomass metallurgy. The fundamentals of biomass pretreatment technology and biomass metallurgy technology were discussed, and the industrial application framework of biomass metallurgy was proposed. Furthermore, the economic and social advantages of biomass metallurgy were analyzed to serve as a reference for the advancement of fundamental theory and industrial application of biomass metallurgy. [ABSTRACT FROM AUTHOR]

In Germany, some digital health applications (DiHA) became reimbursable through the statutory health insurance system with the adoption of the Digital Healthcare Act in 2019. Approaches and concepts for the German care context were developed in an iterative process, based on existing concepts from international experience. A DiHA categorization was developed that could be used as a basis to enable the creation of a reimbursed DiHA repository, and to derive evidence requirements for coverage and reimbursement for each DiHA. The results provide an overview of a possible classification of DiHA as well as approaches to assessment and evaluation. The structure of remuneration and pricing in connection with the formation of groups is demonstrated.

Abstract Background Negative pressure wound therapy (NPWT) is a widely used method of wound treatment. We performed a systematic review of randomised controlled trials (RCTs) comparing the patient-relevant benefits and harms of NPWT with standard wound therapy (SWT) in patients with wounds healing by secondary intention. Methods We searched for RCTs in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and study registries (last search: July 2018) and screened reference lists of relevant systematic reviews and health technology assessments. Manufacturers and investigators were asked to provide unpublished data. Eligible studies investigated at least one patient-relevant outcome (e.g. wound closure). We assessed publication bias and, if feasible, performed meta-analyses, grading the results into different categories (hint, indication or proof of a greater benefit or harm). Results We identified 48 eligible studies of generally low quality with evaluable data for 4315 patients and 30 eligible studies with missing data for at least 1386 patients. Due to potential publication bias (proportion of inaccessible data, 24%), we downgraded our conclusions. A meta-analysis of all wound healing data showed a significant effect in favour of NPWT (OR 1.56, 95% CI 1.15 to 2.13, p = 0.008). As further analyses of different definitions of wound closure did not contradict that analysis, we inferred an indication of a greater benefit of NPWT. A meta-analysis of hospital stay (in days) showed a significant difference in favour of NPWT (MD − 4.78, 95% CI − 7.79 to − 1.76, p = 0.005). As further analyses of different definitions of hospital stay/readmission did not contradict that analysis, we inferred an indication of a greater benefit of NPWT. There was neither proof (nor indication nor hint) of greater benefit or harm of NPWT for other patient-relevant outcomes such as mortality and adverse events. Conclusions In summary, low-quality data indicate a greater benefit of NPWT versus SWT for wound closure in patients with wounds healing by secondary intention. The length of hospital stay is also shortened. The data show no advantages or disadvantages of NPWT for other patient-relevant outcomes. Publication bias is an important problem in studies on NPWT, underlining that all clinical studies need to be fully reported.

Abstract Background All non-sensitized Rhesus D (RhD)-negative pregnant women in Germany receive antenatal anti-D prophylaxis without knowledge of fetal RhD status. Non-invasive prenatal testing (NIPT) of cell-free fetal DNA in maternal plasma could avoid unnecessary anti-D administration. In this paper, we systematically reviewed the evidence on the benefit of NIPT for fetal RhD status in RhD-negative pregnant women. Methods We systematically searched several bibliographic databases, trial registries, and other sources (up to October 2019) for controlled intervention studies investigating NIPT for fetal RhD versus conventional anti-D prophylaxis. The focus was on the impact on fetal and maternal morbidity. We primarily considered direct evidence (from randomized controlled trials) or if unavailable, linked evidence (from diagnostic accuracy studies and from controlled intervention studies investigating the administration or withholding of anti-D prophylaxis). The results of diagnostic accuracy studies were pooled in bivariate meta-analyses. Results Neither direct evidence nor sufficient data for linked evidence were identified. Meta-analysis of data from about 60,000 participants showed high sensitivity (99.9%; 95% CI [99.5%; 100%] and specificity (99.2%; 95% CI [98.5%; 99.5%]). Conclusions NIPT for fetal RhD status is equivalent to conventional serologic testing using the newborn’s blood. Studies investigating patient-relevant outcomes are still lacking.

Background: Due to new legal requirements, a patient-relevant benefit for other wound treatment products (sPW) must be demonstrated through clinical studies if reimbursement at the expense of the statutory health insurance is sought in the non-inpatient sector., Method: An interdisciplinary group with expertise in clinical wound care has developed general recommendations for the design of suitable studies. In addition to regulatory documents, previous studies that have already been recognized as proof of benefit in other areas served as a basis., Results: Randomized controlled trials that cover at least the most common types of chronic wounds (arterial, venous, diabetic or pressure sore) are recommended as the best method for gathering evidence. Despite the heterogeneous etiology of chronic wounds, the results should also be transferable to other wound types. The test intervention does not usually consist of the sPW alone, but of a combined wound treatment that follows a treatment plan that is as clearly defined as possible. In the comparison group, all wound treatment options (besides the sPW) must also be available and used according to a similar predefined treatment plan. Depending on the intended purpose and treatment goal, complete wound closure should, if possible, be recorded as the cardinal - although not always as the primary - endpoint. In justified cases, e.g. in the case of intermediate use as part of phase-appropriate wound therapy for chronic wounds, a significant reduction in the wound area can also be considered for benefit assessment. Quality of life (e.g. pain) can also justify a benefit and can therefore be recorded as a primary outcome parameter in clinical trials. The duration of the clinical trial should be adapted to the central endpoints, the medical or nursing goal of wound care and the intended purpose of the sPW. A benefit does not always arise from microbiological, physiological, laboratory or histological parameters or imaging findings., (© 2024. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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Reducing fuel consumption is a unifying goal across the aviation industry. One fuel-saving opportunity for airlines is reducing contingency fuel loading by dispatchers. Many airlines' flight planning systems (FPSs) provide recommended contingency fuel for dispatchers in the form of statistical contingency fuel (SCF). However, because of limitations of the current SCF estimation procedure, the application of SCF is limited. In this study, we propose to use quantile regression–based machine learning methods to account for fuel burn uncertainties and estimate more reliable SCF values. Utilizing a large fuel burn data set from a major U.S.-based airline, we find that the proposed quantile regression method outperforms the airline's FPS. The benefit of applying the improved SCF models is estimated to be in the range $19 million–$65 million in fuel expense savings as well as 132 million–451 million kilograms of carbon dioxide emission reductions per year, with the lower savings being realized even while maintaining the current, extremely low risk of tapping the reserve fuel. The proposed models can also be used to predict benefits from reduced fuel loading enabled by increasing system predictability, for example, with improved air traffic management. [ABSTRACT FROM AUTHOR]

Traditional customized buses travel on fixed routes, which cannot satisfy passengers' flexibility and convenience requirements. This paper studies a demand-responsive transit (DRT) service that can continuously adjust the path based on passengers' dynamic demand. The path optimization model is established with more realistic constraints to create a bus travel plan within a specified area, and the model not only considers the preferred time windows of passengers but also maximizes the benefits of the system. Based on simulated annealing, a dynamic genetic algorithm is designed to generate the static initial travel path, and the dynamic travel path is continuously updated to satisfy the real-time demand. To evaluate the proposed model and algorithm, a case study in a typical residential community of Beijing, China, is conducted based on transit smart card records. According to the case study results, the convenience, travel time, and economic and environmental benefits of the DRT service are assessed via comparison with traditional buses and private cars. The analysis results demonstrate the feasibility and significance of the method, and it can be used by transit planners to design a superior DRT service. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinical benefit of positron emission tomography (PET)/computed tomography (CT) in patients with advanced melanoma, primarily not selected for surgery based on management changes and survival data using the linked evidence approach (LEA). Methods: A total of 201 18F-FDG PET/CT examinations (n = 33, stage III and n = 168, stage IV) in 119 melanoma patients, primarily not scheduled for surgery, were analysed regarding their impact on clinical management. Patients were selected from a prospective oncological PET/CT registry. The three PET/CT indication groups included unclear lesions in conventional imaging (n = 8), routine follow-up after multiple surgeries (n = 115) and therapy response evaluation of systemic therapy (n = 78). PET/CT-induced management changes were categorized either as major (change from follow-up to surgical or systemic treatment or vice versa, change from surgery to systemic therapy or vice versa) or minor (modifications in systemic therapy). The expected benefit of changes was determined via the linked evidence approach (LEA) connecting registry data, outcome data including overall survival and evidence of diagnostic accuracy of PET/CT based on existing literature. Results: Related to the total study cohort, a change of management after PET/CT was observed in 48% of scans, including 10% minor and 38% major changes. Major changes involved a shift either from follow-up (33/201) or therapy pause (7/201) to systemic therapy, to surgical or other local therapy (26/201) and BSC (2/201). Nine out of 201 cases resulted in treatment pause of systemic therapy. We could confirm the prognostic value of PET/CT-based management by observing a 5-year survival rate more than roughly doubled in patients followed up after tumour exclusion or under local therapy compared with patients under systemic therapy. We could argue for a patient benefit from PET/CT-based management changes using results on accuracy and therapeutic effects from the literature. Conclusion: The use of PET/CT in advanced melanoma patients, primarily not considered for surgery, resulted in frequent changes of management associated with a relevant expected clinical benefit especially in patients classified by PET/CT as tumour-free or eligible for radical surgery. [ABSTRACT FROM AUTHOR]

In this paper we analyze the Russo-Williamson Thesis (RWT) as a standard of evidence in regulatory science, in risk as well as benefit assessment. In our analysis we take account of the recent controversies that have taken place in regulation with respect to the evidentiary requirements necessary for regulatory decision making. RWT's main point is that not only probabilistic but also mechanistic evidence is necessary for being able to infer the existence of causal links. We ask in which way RWT could have an impact upon current decision making about subjecting to regulation (or, to the contrary, leaving them unregulated) certain chemical substances, food stuffs, health claims, and other typical objects of regulation. We show that the application of RWT resolves some of the problems posed by current standards of evidence. RWT makes it possible to determine with higher accuracy if a particular substance should be subjected to regulation or not, even though under certain circumstances RWT itself may turn into a source of regulatory error. The adequacy of RWT as a standard of evidence depends on the precise manner of its application to regulation (particularly the consideration of mechanistic evidence as a complementary or necessary requirement), as well as the assessment of its non-epistemic consequences. • We analyze the implications of applying the Russo-Williamson Thesis (RWT) on causality to regulatory science. • RWT requires both probabilistic and mechanistic kinds of evidence for the establishment of causal claims. • We argue that implementing RWT means a tightening of the standards of evidence for risk and benefit assessment, and might imply an increase in false negatives. • Requiring stricter standards of evidence in risk and benefit assessment consequently, at least under certain circumstances, could be detrimental to public health. [ABSTRACT FROM AUTHOR]

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Ecological restoration refers to the containment of soil erosion, restoration of water conservation, climate regulation, maintenance of ecological functions of biodiversity, and improvement of ecological environment and landscape pattern based on self-repairing capacity of the nature and combined with appropriate artificial measures. Since the natural restoration process of karst desertification mountain is very long, it needs to be supplemented by artificial vegetation restoration. This paper introduced the ecological restoration technologies implemented in karst rocky desertification mountains in Xixiu District, Anshun City of Guizhou Province, and also introduced the afforestation tending management measures. It assessed the ecological benefits of the ecological restoration project from five aspects: mountain community characteristics, vegetation coverage, species diversity, afforestation survival rate and landscape effect. [ABSTRACT FROM AUTHOR]

The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit‐risk ratio. The statistical analysis of AEs is complicated by the fact that the follow‐up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow‐up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta‐analyses of AE data and sketch possible solutions. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate the impact of PET/CT on clinical management of cancer patients based on a prospective data registry. The study was developed to inform consultations with public health insurances on PET/CT coverage.Methods: We evaluated a prospective patient cohort having a clinically indicated PET/CT at a single German University Center from April 2013 to August 2016. The registry collected questionnaire data from requesting physicians on intended patient management before and after PET/CT. A total of 4,504 patients with 5,939 PET/CT examinations were enrolled in the registry, resulting in evaluable data from 3,724 patients receiving 4,754 scans. The impact of PET/CT on patient management was assessed across 22 tumor types, for different indications (diagnosis, staging, suspected recurrence) and different categories of management including treatment (curative or palliative) and non-treatment (watchful waiting, additional imaging, invasive tests).Results: The most frequent PET/CT indication was tumor staging (59.7%). Melanoma, lung cancer, lymphoma, neuroendocrine tumor and prostate cancer accounted for 70% of cases. Overall, the use of PET/CT resulted in a 37.1% change of clinical management (95% CI, 35.7-38.5), most frequently (30.6%) from an intended non-treatment strategy before PET/CT to active treatment after PET/CT. The frequency of changes ranged from 28.3% for head and neck cancers up to 46.0% for melanomas. The impact of PET/CT was greatest in reducing demands for additional imaging which decreased from 66.1% before PET/CT to 6.1% after PET/CT. Pre-PET/CT planned invasive tests could be avoided in 72.7% of cases. The treatment goal changed after PET/CT in 21.7% of cases, in twice as many cases from curative to palliative therapy than vice versa.Conclusions: The data of this large prospective registry confirm that physicians often change their intended management on the basis of PET/CT by initiating treatment and reducing additional imaging as well as invasive tests. This applies to various cancer types and indications. [ABSTRACT FROM AUTHOR]

Developing a regional power system to achieve a high level of integration of national systems requires sufficient development of the regional transmission grid. This is possible only with appropriate schemes for the complete cost−benefit analyses, and cost allocation of these transmission investments, which plays a critical role in the selection of the most efficient network investment and the proper assignment of their cost to the national systems. Network reinforcements affect the operation of power systems and, therefore, the externalities of power generation. This paper examines the impacts of integrating local air pollution damage from power production within the benefit assessment and cost allocation of transmission investments. The paper describes the methodology followed and illustrates its application in a real-life case study where a simplified version of a European network is considered. Within this case study, we have assessed the impact of considering the reduction in air pollution damage achieved through a particular HVDC project between France and Spain on the benefits, and benefit-driven cost allocation, computed for this project. In this case study, local pollution related benefits are a relevant fraction of the overall benefits of the considered transmission project. However, considering the local air pollution benefits of the project does not affect the net positive benefits of each country significantly, resulting in a limited change in the cost allocation of the project.

Highlights • Apply ensemble learning techniques to improve airline fuel burn prediction. • Propose a prediction interval based discretionary fuel estimation approach. • The new approach can achieve $61 million annual fuel savings for the study airline. • CO 2 emission can also be reduced by 428 million kg per year for the study airline. Abstract Reducing fuel consumption is a unifying goal across the aviation industry. One fuel-saving opportunity for airlines is the possibility of reducing discretionary fuel loading by dispatchers. In this study, we propose a novel discretionary fuel estimation approach that can assist dispatchers with better discretionary fuel loading decisions. Based on the analysis on our study airline, our approach is found to substantially reduce unnecessary discretionary fuel loading while maintaining the same safety level compared to the current fuel loading practice. The idea is that by providing dispatchers with more accurate information and better recommendations derived from flight records, unnecessary fuel loading and corresponding cost-to-carry could both be reduced. We apply ensemble learning techniques to improve fuel burn prediction and construct prediction intervals (PIs) to capture the uncertainty of model predictions. The upper bound of a PI can then be used for discretionary fuel loading. The potential benefit of this approach is estimated to be $61.5 million in fuel savings and 428 million kg of CO 2 reduction per year for our study airline. This study also builds a link between discretionary fuel estimation and aviation system predictability in which the proposed models can also be used to predict benefits from reduced fuel loading enabled by improved Air Traffic Management (ATM) targeting on improved system predictability. [ABSTRACT FROM AUTHOR]

Highlights • B£ST values benefits using ES for nature based measures for stormwater management. • Uncertainties are illustrated for financial valuation of green stormwater management measures. • Decision makers and advisors need to engage in facing the uncertainties in valuations. Abstract Blue and green infrastructure (BGI) provides a wide range of ecosystem services (ES) and other benefits when managing stormwater, beyond flow and pollution control. A number of tools have been developed to value these benefits. In the UK, stormwater measures that utilise BGI are known as Sustainable Drainage Systems (SuDS). This paper outlines the Benefits of SuDS Tool (B£ST), developed in the UK by the Construction Industry Research and Information Association (CIRIA) for valuing the benefits of BGI stormwater measures. The tool has been applied to case studies across Europe. B£ST includes a set of benefits based on ecosystem services applied to the use of BGI for stormwater management. The paper focuses on the uncertainties in this multiple benefit assessment, detailing the processes used in the tool. Examples illustrate the scale of the uncertainties in tools like B£ST. The uncertainties when using BGI valuation tools such as B£ST to help inform the delivery of stormwater measures are demonstrated in the paper as potentially of sufficient magnitude to warrant explicit consideration by professionals and decision makers. [ABSTRACT FROM AUTHOR]

With the growth of air traffic, airport surfaces are congested and air traffic operations are disrupted by the formation of bottlenecks on the surface. Hence, improving the efficiency and predictability of airport surface operations is not only a key goal of NASA’s initiatives in Integrated Arrival/Departure/Surface (IADS) operations, but also has been recognized as a critical aspect of the FAA NextGEN implementation plan. While a number of tactical initiatives have been shown to be effective in improving airport surface operations from a service provider’s perspective, their impacts on airlines’ scheduled block time (SBT) setting, which has been found to have direct impact on airlines’ on-time performance and operating cost, have received little attention. In this paper, we assess this impact using an econometric model of airline SBT combined with a before/after analysis of the implementation of surface congestion management (SCM) at John F. Kennedy International Airport (JFK) in 2010. Since airlines do not consider gate delay in setting SBT, we find that reduction in taxi-out time variability resulting from SCM leads to more predictable taxi-out times and thus decreases in SBT. The JFK SCM implementation is used as a case study to validate model prediction performance. The observed SBT decrease between 2009 and 2011 at JFK is 4.8 min and our model predicts a 4.2 min decrease. In addition, Charlotte Douglas International Airport (CLT) is used as an example to demonstrate how different surface operations improvements scenarios can be evaluated in terms of SBT reduction. [ABSTRACT FROM AUTHOR]

Predictability in the aviation system affects costs to airlines and passengers. We propose a predictability metric based on a flight's gate-in fuel (GIF) which can be directly measured and monetized by aviation stakeholders. We estimate GIF for six major U.S. airlines. Since GIF data are not directly available, we develop an estimation methodology to obtain GIF from pushback weight and fuel burn, including a conversion from passenger to weight payload based on an econometric model. The methodology accounts for aircraft operating empty weight and payload. We find that GIF varies across airlines and time of year, and is highest during the summer period. We monetize GIF through a cost-to-carry analysis as extra fuel loading results in additional fuel burn. Our estimates reveal that, in 2012, airlines spent an additional $59 million to $667 million on carrying GIF, with a total across all six airlines of $1.46 billion. [ABSTRACT FROM AUTHOR]