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In the current context of the pandemic triggered by SARS-COV-2, the immunization of the population through vaccination is recognized as a public health priority. In the case of SARS-COV-2, the genetic sequencing was done quickly, in one month. Since then, worldwide research has focused on obtaining a vaccine. This has a major economic impact because new technological platforms and advanced genetic engineering procedures are required to obtain a COVID-19 vaccine. The most difficult scientific challenge for this future vaccine obtained in the laboratory is the proof of clinical safety and efficacy. The biggest challenge of manufacturing is the construction and validation of production platforms capable of making the vaccine on a large scale.

PurposeBevacizumab is a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor-specific angiogenesis in some cancers. MYL-1402O is a proposed bevacizumab biosimilar.MethodsThe primary objective of this single-center, randomized, double-blind, three-arm, parallel-group, phase 1 study in healthy male volunteers was to evaluate bioequivalence of MYL-1402O to EU and US-reference bevacizumab, and EU-reference bevacizumab to US-reference bevacizumab. The primary pharmacokinetic parameter was area under the serum concentration–time curve from 0 extrapolated to infinity (AUC0–∞). Pharmacokinetic parameters were analyzed using general linear models of analysis of variance. Secondary endpoints included safety and tolerability.ResultsOf 111 enrolled subjects, 110 were included in the pharmacokinetic analysis (MYL-1402O, n = 37; EU-reference bevacizumab, n = 36; US-reference bevacizumab, n = 37). Bioequivalence was demonstrated between MYL-1402O and EU-reference bevacizumab, MYL-1402O and US-reference bevacizumab, and between EU- and US-reference bevacizumab where least squares mean ratios of AUC0–∞ were close to 1, and 90% CIs were within the equivalence range (0.80–1.25). Secondary pharmacokinetic parameters (AUC from 0 to time of last quantifiable concentration [AUC0–t], peak serum concentration [Cmax], time to Cmax, elimination rate constant, and elimination half-life) were also comparable, with 90% CIs for ratios of AUC0–t and Cmax within 80–125%. Treatment-emergent adverse events were similar across all three treatment groups and were consistent with clinical data for bevacizumab.ConclusionMYL-1402O was well tolerated and demonstrated pharmacokinetic and safety profiles similar to EU-reference bevacizumab and US-reference bevacizumab in healthy male volunteers. No new significant safety issues emerged (ClinicalTrials.gov, NCT02469987; ClinicalTrialsRegister.eu EudraCT, 2014-005621-12; June 12, 2015).

While there is evidence for an acceleration in global mean sea level (MSL) since the 1960s, its detection at local levels has been hampered by the considerable influence of natural variability on the rate of MSL change. Here we report a MSL acceleration in tide gauge records along the U.S. Southeast and Gulf coasts that has led to rates (>10 mm yr −1 since 2010) that are unprecedented in at least 120 years. We show that this acceleration is primarily induced by an ocean dynamic signal exceeding the externally forced response from historical climate model simulations. However, when the simulated forced response is removed from observations, the residuals are neither historically unprecedented nor inconsistent with internal variability in simulations. A large fraction of the residuals is consistent with wind driven Rossby waves in the tropical North Atlantic. This indicates that this ongoing acceleration represents the compounding effects of external forcing and internal climate variability. Sea level rise along the U.S. Southeast and Gulf Coast has accelerated since 2010 due to changes in steric expansion and the ocean’s circulation. The acceleration represents the compounding effects of external forcing and natural climate variability.

Sea level rise (SLR), a well-documented and urgent aspect of anthropogenic global warming, threatens population and assets located in low-lying coastal regions all around the world. Common flood hazard assessment practices typically account for one driver at a time (e.g., either fluvial flooding only or ocean flooding only), whereas coastal cities vulnerable to SLR are at risk for flooding from multiple drivers (e.g., extreme coastal high tide, storm surge, and river flow). Here, we propose a bivariate flood hazard assessment approach that accounts for compound flooding from river flow and coastal water level, and we show that a univariate approach may not appropriately characterize the flood hazard if there are compounding effects. Using copulas and bivariate dependence analysis, we also quantify the increases in failure probabilities for 2030 and 2050 caused by SLR under representative concentration pathways 4.5 and 8.5. Additionally, the increase in failure probability is shown to be strongly affected by compounding effects. The proposed failure probability method offers an innovative tool for assessing compounding flood hazards in a warming climate.

Background Robotic systems for chemotherapy preparation offer improved accuracy and staff safety but require substantial capital investment. This study assessed the economic performance of a domestically developed robotic chemotherapy compounding system at Udon Thani Cancer Hospital and its service expansion to a network hospital in Thailand. Methods A descriptive study with economic evaluation was conducted, including cost–benefit analysis, unit cost analysis, and break-even analysis from both provider and health system perspectives. Data from fiscal year 2023 were used. Direct and indirect costs were assessed, and clinical outcomes were documented. A scenario-based sensitivity analysis was performed to examine cost variations under different capacity utilisation levels. Results Robotic preparation had a higher per-dose cost (THB 538 for 4,173 doses) than manual preparation (THB 250 for 20,310 doses), but was associated with total estimated economic benefits of THB 1.88 million, including labour and training savings and improved pharmaceutical care. The break-even point was estimated at 41,802 doses for robotic compounding and 5,122 doses for service expansion. The incremental benefit–cost ratio (IBCR) was 1.566 and increased to 3.018 when including delivery to the network hospital. Conclusions The robotic system demonstrated potential economic and operational advantages, particularly when scaled to serve additional facilities. These findings offer preliminary evidence to inform future policy considerations under Thailand’s Cancer Service Plan. Further evaluation is needed to assess long-term sustainability and broader system-level outcomes.

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such an extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry.

Aiming at the application limitations of single slump-retaining mother liquor in complex construction scenarios, this study innovatively proposes a compounding technology for three types of slump-retaining mother liquors (early-stage, mid-stage, and late-stage) and develops a novel composite slump-retaining product. Through systematic orthogonal experiments and mechanistic analysis, the optimal compounding ratio of the three mother liquors is determined, while the synergistic dosages of retarder and air-entraining agent are optimized. The results indicate that when the early-stage, mid-stage, and late-stage slump-retaining mother liquors are compounded at a ratio of 5:2:7, combined with 30 kg/t retarder and 0.6 kg/t air-entraining agent, the composite system can effectively control the time-dependent loss of concrete slump flow and enhance the comprehensive performance of the slump-retaining product. This innovative technology provides a solution with both engineering applicability and technical advancement for the field of concrete slump retention, which is of great significance for promoting the development of high-performance concrete construction technologies.

By combining long-term ground-based data on water withdrawal with climate model projections, this study quantifies the compounding effects of human activities and climate change on surface water availability in Iran over the twenty-first century. Our findings show that increasing water withdrawal in Iran, due to population growth and increased agricultural activities, has been the main source of historical water stress. Increased levels of water stress across Iran are expected to continue or even worsen over the next decades due to projected variability and change in precipitation combined with heightened water withdrawals due to increasing population and socio-economic activities. The greatest rate of decreased water storage is expected in the Urmia Basin, northwest of Iran, (varying from ~ − 8.3 mm/year in 2010–2039 to ~ − 61.6 mm/year in 2070–2099 compared with an observed rate of 4 mm/year in 1976–2005). Human activities, however, strongly dominate the effects of precipitation variability and change. Major shifts toward sustainable land and water management are needed to reduce the impacts of water scarcity in the future, particularly in Iran’s heavily stressed basins like Urmia Basin, which feeds the shrinking Lake Urmia.

Cellulose nanomaterials (CNs) are an emerging class of materials with numerous potential applications, including as additives or reinforcements for thermoplastics. Unfortunately, the preparation of CNs typically results in dilute, aqueous suspensions, and the lack of efficient water removal methods has hindered commercialization. However, water may also present opportunities for improving overall efficiencies if its potential is better understood and if it is better managed through the various stages of CN and composite production. Wet compounding represents one such possible opportunity by leveraging water’s ability to aid in CN dispersion, act as a transport medium for metering and feeding of CNs, plasticize some polymers, or potentially facilitate the preparation of CNs during compounding. However, there are also considerable challenges and much investigation remains. Here, we review various wet compounding approaches used in the preparation of cellulose nanocomposites as well as the related concepts of wet feeding and wet extrusion fibrillation of cellulose. We also discuss potential opportunities, remaining challenges, and research and development needs with the ultimate goal of developing a more integrated approach to cellulose nanocomposite preparation and a more sophisticated understanding of water’s role in the compounding process.

Compound weather and climate events are combinations of climate drivers and/or hazards that contribute to societal or environmental risk. Studying compound events often requires a multidisciplinary approach combining domain knowledge of the underlying processes with, for example, statistical methods and climate model outputs. Recently, to aid the development of research on compound events, four compound event types were introduced, namely (a) preconditioned, (b) multivariate, (c) temporally compounding, and (d) spatially compounding events. However, guidelines on how to study these types of events are still lacking. Here, we consider four case studies, each associated with a specific event type and a research question, to illustrate how the key elements of compound events (e.g., analytical tools and relevant physical effects) can be identified. These case studies show that (a) impacts on crops from hot and dry summers can be exacerbated by preconditioning effects of dry and bright springs. (b) Assessing compound coastal flooding in Perth (Australia) requires considering the dynamics of a non‐stationary multivariate process. For instance, future mean sea‐level rise will lead to the emergence of concurrent coastal and fluvial extremes, enhancing compound flooding risk. (c) In Portugal, deep‐landslides are often caused by temporal clusters of moderate precipitation events. Finally, (d) crop yield failures in France and Germany are strongly correlated, threatening European food security through spatially compounding effects. These analyses allow for identifying general recommendations for studying compound events. Overall, our insights can serve as a blueprint for compound event analysis across disciplines and sectors. Plain Language Summary Many societal and environmental impacts from events such as droughts and storms arise from a combination of weather and climate factors referred to as a compound event. Considering the complex nature of these high‐impact events is crucial for an accurate assessment of climate‐related risk, for example to develop adaptation and emergency preparedness strategies. However, compound event research has emerged only recently, therefore our ability to analyze these events is still limited. In practice, studying compound events is a challenging task, which often requires interaction between experts across multiple disciplines. Recently, compound events were divided into four types to aid the framing of research on this topic, but guidelines on how to study these four types are missing. Here, we take a pragmatic approach and—focusing on case studies of different compound event types—illustrate how to address specific research questions that could be of interest to users. The results allow identifying recommendations for compound event analyses. Furthermore, through the case studies, we highlight the relevance that compounding effects have for the occurrence of landslides, flooding, vegetation impacts, and crop failures. The guidelines emerged from this work will assist the development of compound event analysis across disciplines and sectors. Key Points Using case studies representative of four main compound event types we show how compound event‐related research questions can be tackled We present user‐friendly guidelines for compound event analysis applicable to different compound event types We demonstrate that compound events cause vegetation impacts, coastal flooding, landslides, and continental‐scale crop yield failures