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Biological therapies have transformed high-burden treatments. As the patent and exclusivity period for biological medicines draws to a close, there is a possibility for the development and authorization of biosimilars. These products boast comparable levels of safety, quality, and effectiveness to their precursor reference products. Biosimilars, although similar to reference products, are not identical copies and should not be considered generic substitutes for the original. Their development and evaluation involve a rigorous step-by-step process that includes analytical, functional, and nonclinical evaluations and clinical trials. Clinical studies conducted for biosimilars aim to establish similar efficacy, safety, and immunogenicity, rather than demonstrating a clinical benefit, as with the reference product. However, although the current knowledge regarding biosimilars has significantly increased, several controversies and misconceptions still exist regarding their immunogenicity, extrapolation, interchangeability, substitution, and nomenclature. The development of biosimilars stimulates market competition, contributes toward healthcare sustainability, and allows for greater patient access. However, maximizing the benefits of biosimilars requires cooperation between regulators and developers to ensure that patients can benefit quickly from access to these new therapeutic alternatives while maintaining high standards of quality, safety, and efficacy. Recognizing the inherent complexities of comprehending biosimilars fully, it is essential to focus on realistic approaches, such as fostering open communication between healthcare providers and patients, encouraging informed decision-making, and minimizing risks. This review addresses the regulatory and manufacturing requirements for biosimilars and provides clinicians with relevant insights for informed prescribing.

This study provides a systematic comparative analysis of seven common cross-national measures of state capacity by focusing on three measurement issues: convergent validity, interchangeability, and case-specific disagreement. The author finds that the convergent validity of the measures is high, but the interchangeability of the measures is low. This means that even highly correlated measures of state capacity can lead to completely different statistical inferences. The cause of this puzzling finding lies in strikingly large disagreements on some of the country scores. The author shows that these disagreements depend on two factors: differences in underlying components and the level of state capacity. Considering the findings of this study, users of measures of state capacity must not assume that any highly correlated indicator is appropriate. They should instead look at what the indicators actually measure and ensure that a given definition of state capacity matches the chosen indicator.

The injection of green hydrogen and biomethane is currently seen as the next step towards the decarbonization of the gas sector in several countries. However, the introduction of these gases in existent infrastructure has energetic, material and operational implications that should be carefully looked at. With regard to a fully blown green gas grid, transport and distribution will require adaptations. Furthermore, the adequate performance of end-use equipment connected to the grid must be accounted for. In this paper, a technical analysis of the energetic, material and operational aspects of hydrogen and biomethane introduction in natural gas infrastructure is performed. Impacts on gas transmission and distribution are evaluated and an interchangeability analysis, supported by one-dimensional Cantera simulations, is conducted. Existing gas infrastructure seems to be generally fit for the introduction of hydrogen and biomethane. Hydrogen content up to 20% by volume appears to be possible to accommodate in current infrastructure with only minor technical modifications. However, at the Distribution System Operator (DSO) level, the introduction of gas quality tracking systems will be required due to the distributed injection nature of hydrogen and biomethane. The different tolerances for hydrogen blending of consumers, depending on end-use equipment, may be critical during the transition period to a 100% green gas grid as there is a risk of pushing consumers off the grid.

By comparing and analysing four cross-national measures of democracy, this article provides novel information regarding the statistical properties, convergence, and interchangeability of some of the most frequently used measures of democracy. The author points out limitations related to the statistical properties of these measures and finds that even if measures of democracy are highly convergent, their interchangeability is weak. This means that the choice of the measure of democracy has considerable consequences for the conclusions of a given study. Especially so in studies covering the last few decades, because the author finds that in general the interchangeability of democracy measures has decreased since the 1980s. In choosing one measure over another, scholars should be aware of the limitations identified in this article. To overcome problems related to weak interchangeability, if a single measure cannot be credibly chosen on theoretical grounds, the author recommends users of the measures to validate their findings with multiple measures of democracy.

Competition arising from the increasing availability of biosimilar medicines has resulted in healthcare savings and has provided greater patient access to high cost therapeutics in Europe. The biosimilar market in the USA is relatively new so the full impact of biosimilar availability remains to be seen. Educational initiatives relating to the use of biosimilar medicines are currently being undertaken by regulators, policy makers and industry. The debate on biosimilars has moved on from the appropriateness of the regulatory framework which governs their approval, to the practice of interchangeability. Interchangeability is an important issue for healthcare professionals but different definitions and regulatory frameworks exist in the USA and Europe. In the USA, an interchangeable biological product is a biosimilar which may be substituted by a pharmacist, subject to local State policies. The interchangeability of a biosimilar with its reference medicine will be evaluated by the United States Food and Drug Administration (FDA) in cases where approval as an ‘interchangeable product’ is sought. In contrast, the European Medicines Agency (EMA) does not assess or make recommendations on interchangeability, therefore, in Europe, interchangeability does not mean substitution but is generally physician-led or driven by national policy. This paper provides an overview of the regulation of biosimilar medicines. Challenges associated with the demonstration of interchangeability and practical considerations relating to switching are also discussed. Finally, we present policies that have been adopted to date in several European countries, the USA and Australia, which aim to promote the use of biosimilar medicines.

Although biosimilars have been part of clinical practice for more than a decade, healthcare professionals (HCPs) do not fully accept them. This is because of the perception that biosimilars may not be like their originators in terms of quality, safety, and efficacy. This study aims to evaluate the current knowledge and attitudes of healthcare professionals toward biosimilar prescription, and to elaborate on their concerns. We reviewed the literature using PubMed, Cochrane Library, and Science Direct electronic databases in the period from 2018 to 2020. The knowledge and confidence of healthcare professionals vary between countries, between clinical profiles and between studies. Although most of the healthcare professionals had a positive attitude to prescribing biosimilars, they would still prefer to prescribe them in initial treatment. Generally, HCPs were against multiple switches and substitution of biosimilars at the pharmacy level. HCP’s key concern was interchangeability, with eventual consequences on the clinical outcome of patients. HCPs still approach biosimilars with caution and stigma. HCPs need to have an unbiased coherent understanding of biosimilars at clinical, molecular and regulatory levels. It was also observed that most of their concerns are more theoretical than science-based. Physicians are in an excellent position to accept biosimilars, but they need the additional support of regulatory authorities to approve and take into consideration the available scientific data regarding biosimilars.

We investigate the concept of adjustability—the difference in objective values between two types of dynamic robust optimization formulations: one where (static) decisions are made before uncertainty realization, and one where uncertainty is resolved before (adjustable) decisions. This difference reflects the value of information and decision timing in optimization under uncertainty, and is related to several other concepts such as the optimality of decision rules in robust optimization. We develop a theoretical framework to quantify adjustability based on the input data of a robust optimization problem with a linear objective, linear constraints, and fixed recourse. We make very few additional assumptions. In particular, we do not assume constraint-wise separability or parameter nonnegativity that are commonly imposed in the literature for the study of adjustability. This allows us to study important but previously under-investigated problems, such as formulations with equality constraints and problems with both upper and lower bound constraints. Based on the discovery of an interesting connection between the reformulations of the static and fully adjustable problems, our analysis gives a necessary and sufficient condition—in the form of a theorem-of-the-alternatives—for adjustability to be zero when the uncertainty set is polyhedral. Based on this sharp characterization, we provide two efficient mixed-integer optimization formulations to verify zero adjustability. Then, we develop a constructive approach to quantify adjustability when the uncertainty set is general, which results in an efficient and tight poly-time algorithm to bound adjustability. We demonstrate the efficiency and tightness via both theoretical and numerical analyses.

This paper investigates the geometric interchangeability and dimensional precision of parts fabricated using Fused Deposition Modeling (FDM), with a focus on gear manufacturing. By employing a substrate and two spur gears as test components, critical process parameters, including layer thickness, extrusion speed, and print temperature, were optimized to achieve enhanced accuracy. Geometric and dimensional tolerances such as straightness, roundness, and surface roughness were systematically evaluated using advanced metrological techniques. The results indicate that larger components demonstrate higher precision, with deviations for large and pinion gears ranging between −0.045 and 0.060 mm, and −0.150 and 0.078 mm, respectively. Analysis reveals that the anisotropic nature of the FDM process and thermal shrinkage significantly impact accuracy, particularly in smaller features. Residual stress analysis reveals that smaller components formed via FDM exhibit higher stress concentrations and dimensional deviations due to voids and uneven thermal contraction, whereas larger components and flat substrates achieve better stress distribution and precision. The findings suggest that reducing material shrinkage coefficients and optimizing process parameters can enhance part quality, achieving dimensional tolerances within ±0.1 mm and geometric consistency suitable for practical applications. This research highlights the potential of FDM for precision manufacturing and provides insights into improving its performance for high-demand industrial applications.

SummaryIntroductionBioequivalence between a reference and a generic drug is based on the hypothesis that a ± 20% change in blood exposure (or ± 10% for drugs with narrow therapeutic index, NTI) following the generic/reference switch will not have any therapeutic consequences. However, the individual exposure ratio between generic and reference can be higher than 1.20 (or 1.10). This study aims to analyse the different parameters influencing the individual exposure ratio, hence the conditions for reference/generic interchangeability.MethodsBioequivalence studies with a double cross-over design for a virtual drug were simulated using 100 random sets of 12, 24, 48 or 100 pairs of areas under the curve (AUC), varying the generic/reference AUC geometric mean ratios between 0.80 and 1.25 and the within-subject exposure variance of the reference and the generic formulations.ResultsThe proportion of subjects with an exposure generic/reference ratio outside the ± 10% or ± 20% acceptance intervals increases when (1) the reference within-subject variance increases; (2) the ratio of the generic within-subject variance on the reference within-subject variance increases; and (3) the generic/reference mean AUC ratio diverges from 1.0. When only considering replicated administrations of the reference, the individual exposure ratio increases with the within-subject variance, yielding values outside the usually accepted individual exposure ratio range of 0.5 to 2 for drugs with narrow therapeutic index as soon as the within-subject variance standard deviation is ≥ 0.25 (equivalent to within-patient CV% > 25%).ConclusionsInterchangeability between reference and generic formulations, especially for drugs with narrow therapeutic index can only be assumed if, the within-subject variance of generic is less or equal to the within-subject variance of reference or, if this is not the case, if the distribution of the generic/generic individual exposure ratios is included within the therapeutic margins of the reference drug.

Sex-specific trait expression is frequently associated with highly variable, condition-dependent expression within sexes and rapid divergence among closely related species. Horned beetles are an excellent example for studying the molecular basis of these phenomena because horn morphology varies markedly among species, between sexes, and among alternative, nutritionally-cued morphs within sexes. In addition, horns lack obvious homology to other insect traits and provide a good opportunity to explore the molecular basis of the rapid diversification of a novel trait within and between species. Here we show that the sex-determination gene doublesex (dsx) underlies important aspects of horn development, including differences between sexes, morphs, and species. In male Onthophagus taurus , dsx transcripts were preferentially expressed in the horns of the large, horned morph, and RNAi-mediated knockdown of dsx dramatically altered male horn allometry by massively reducing horn development in large males, but not in smaller males. Conversely, dsx RNAi induced ectopic, nutrition-sensitive horn development in otherwise hornless females. Finally, in a closely related species (Onthophagus sagittarius) that has recently evolved a rare reversed sexual dimorphism, dsx RNAi revealed reversed as well as novel dsx functions despite an overall conservation of dsx expression. This suggests that rapid evolution of dsx functions has facilitated the transition from a regular sexual dimorphism to a reversed sexual dimorphism in this species. Our findings add beetle horns to existing examples of a close relationship between dsx and sexual trait development, and suggest that dsx function has been coopted to facilitate both the evolution of environmentally-cued intrasexual dimorphisms and rapid species divergences in a novel trait.