Search Results (52)

Recent outbreaks of highly pathogenic human RNA viruses from probable zoonotic origin have highlighted the relevance of epidemic preparedness as a society. However, research in vaccinology and virology, as well as epidemiologic surveillance, is often constrained by the biological risk that live virus experimentation entails. These also involve expensive costs, time-consuming procedures, and advanced personnel expertise, hampering market access for many drugs. Most of these drawbacks can be circumvented with the use of pseudotyped viruses, which are surrogate, non-pathogenic recombinant viral particles bearing the surface envelope protein of a virus of interest. Pseudotyped viruses significantly expand the research potential in virology, enabling the study of non-culturable or highly infectious pathogens in a safer environment. Most are derived from lentiviral vectors, which confer a series of advantages due to their superior efficiency. During the past decade, many studies employing pseudotyped viruses have evaluated the efficacy of vaccines or monoclonal antibodies for relevant pathogens such as HIV-1, Ebolavirus, Influenza virus, or SARS-CoV-2. In this review, we aim to provide an overview of the applications of pseudotyped viruses when evaluating the neutralization capacity of exposed individuals, or candidate vaccines and antivirals in both preclinical models and clinical trials, to further help develop effective countermeasures against emerging neutralization-escape phenotypes. Full article

The designs of clinical trials of drugs for rare diseases are challenged by health technology assessment organisations and payers. Phase II pivotal studies, single-arm or open-label designs, the extensive use of non-final endpoints, and the limited use of patient-reported outcomes (PROs) are the main points of contention. The evidence on the actual design of these trials is limited, but corroborates the concerns of the above. Our aim is to scrutinise whether the design of pivotal studies of drugs for rare diseases to be launched into the Italian market by 2026 present similar issues. The drugs and the relevant pivotal studies were retrieved from Biomedtracker and US and European clinical trial databases. We identified 154 new drugs for rare diseases. Single-arm designs account for 36% of trials. Almost 50% of randomised control trials (RCTs) are designed using an active comparator and 61% are double-blinded. Primary endpoints are mostly (82%) surrogate. A total of 59% of studies include PROs. Our findings were partially expected (e.g., extensive use of surrogate endpoints) and partially not (e.g., RCTs and an active comparator), considering previous studies on the same topic. Having more head-to-head studies may reduce uncertainty concerning evidence at market launch, but different issues persist, including the still limited role of PROs. Full article

Drylands cover approximately 41% of Earth’s land surface, supporting about 500 million people and 45% of global agriculture. Groundwater is essential in drylands and is crucial for maintaining ecosystem services and offering numerous benefits. This article, for the first time, analyses and valuates the hydrological ecosystem services (HESs) provided by groundwater in a region of the Colorado River Delta in Mexico, an area with uncertain economic impact due to water scarcity. The main water sources are the Colorado River and groundwater from the Mexicali and San Luis Rio Colorado valley aquifers, both of which are overexploited. Valuation techniques include surrogate and simulated market methods for agricultural, industrial, urban, and domestic uses, the shadow project approach for water conservation and purification cost avoidance, and the contingent valuation method for recreation. Data from 2013 to 2015 and 2020 were used as they are the most reliable sources available. The annual value of HESs provided by groundwater was USD 883,520 million, with water conservation being a key factor. The analyzed groundwater uses reflect differences in efficiency and economic value, providing key information for decisions on governance, allocation, conservation, and revaluation of water resources. These results suggest reorienting crops, establishing differentiated rates, and promoting payment for environmental services programs. Full article

Background: Neisseria meningitidis B is one of the main causative pathogens of meningitis and other forms of severe meningococcal disease. In the past decade, meningococcal B vaccines have been developed to address this infection and its sequelae. Objective: This article aims to present an example of how the EU regulatory framework allowed the early authorisation of two life-saving vaccines initially based on immunogenicity surrogates of clinical evidence. This was subsequently followed by post-marketing surveillance providing real-world evidence to support their safety profile and impact on the paediatric population in the EU. Methods: We review the evidence supporting the initial regulatory approval of the vaccines, the confirmatory data demonstrating vaccine effectiveness post-authorisation, and the real-world impact of these vaccines on the paediatric population. Results: Two vaccines were approved in the EU for active immunisation to prevent IMD caused by MenB (4CMenB in 2013 and MenB-fHBP in 2017). Both marketing authorisations were based on immunogenicity data (efficacy studies were not feasible due to the rarity of the disease) and safety data generated from pre-authorisation studies. Additional pharmacovigilance activities to further investigate the safety profile and effectiveness studies were requested to be conducted after approval. Both the effectiveness and safety profile of the vaccines were confirmed by these data. Conclusions: This paper illustrates that the EU medicines regulatory framework and safety monitoring system are robust. By supplementing the initial evidence with post-authorisation studies, further effectiveness and safety data enabled regulators to confirm the positive benefit–risk of the vaccines without delaying their access to the people who need them. Full article

Background/Objectives: We reviewed Post-Marketing Requirements (PMRs) under the Pediatric Research Equity Act (PREA) for antibiotics approved in adults from 2009 to 2024 to better understand factors associated with PMR study completion. Methods: Initial PMRs, including study design and completion timelines were extracted from Food and Drug Administration (FDA) approval letters. Studies were cross-referenced at clinicaltrials.gov, with follow-up from adult approval to study completion or through 31 December 2024. Results: Eighteen antibiotics were approved in adults from 2009 to 2024, with 53 associated PREA PMRs. A total of nine PMRs were excluded from analysis (six exclusions for projected study completion dates on or after 12/31/2024, one exclusion due to lack of information, and two exclusions because the study type was not categorizable as Phase 1 or Phase 2). Of the 44 remaining PMRs in the analysis set, the median pediatric study follow-up time from adult approval was 5.3 years (range 0.94 to 11.5 years), with a study completion rate of 54.5% (N = 24). Small- and medium-sized companies had a study completion rate of 10% (N = 2/20) over a median of 6.44 years of follow-up, with no pediatric approvals. Large pharmaceutical corporations had a significantly higher study completion rate of 91.6% (N = 22/24; adjusted hazard ratio 20.3 95%CI, 5.02 to 82.4) over a median follow-up time of 4.7 years and achieved pediatric approval with labelling updates for 75% of antibiotics (N = 6/8). Conclusions: Compared to larger organizations, smaller pharmaceutical companies have experienced difficulty in PREA PMR antibiotic study completion, which may be related to financial difficulties in the challenging market for antibiotics. To improve PMR study completion, smaller companies require continued financial support and innovation in study design. For pediatric antibiotic development, the FDA accepts the extrapolation of efficacy from well-conducted randomized adult trials (i.e., pharmacokinetics (PK) and the safety approach). Therefore, sponsors should consider the use of single-arm, non-comparative PK and safety study designs to reduce the size and scope of trials. Sponsors should also assess whether the evaluation of an antibiotic is necessary in adolescents, or if data in a surrogate population of adults (e.g., low-weight adults) may serve as adequate evidence for adolescent approval. Full article

This study investigates the multifractal behavior of four leading semiconductor stocks—Intel (INTC), Advanced Micro Devices (AMD), Nvidia (NVDA), and Broadcom (AVGO)—in relation to key financial assets, including the Dow Jones Industrial Average (DJI), the Euro–U.S. Dollar exchange rate (EUR), gold (XAU), crude oil (WTI), and Bitcoin (BTC), using Multifractal Asymmetric Detrended Cross-Correlation Analysis (MF-ADCCA). The analysis is based on daily price return time series from January 2015 to January 2025. Results reveal consistent evidence of multifractality across all asset pairs, with the generalized Hurst exponent exhibiting significant variability, indicative of complex and nonlinear stock price dynamics. Among the semiconductor stocks, NVDA and AVGO exhibit the highest levels of multifractal cross-correlation, particularly with DJI, WTI, and BTC, while AMD consistently shows the lowest, suggesting comparatively more stable behavior. Notably, cross-correlation Hurst exponents with BTC are the highest, reaching approximately 0.54 for NVDA and AMD. Conversely, pairs with EUR display long-term negative correlations, with exponents around 0.46 across all semiconductor stocks. Multifractal spectrum analysis highlights that NVDA and AVGO exhibit broader and more pronounced multifractal characteristics, largely driven by higher fluctuation intensities. Asymmetric cross-correlation analysis reveals that stocks paired with DJI show greater persistence during market downturns, whereas those paired with XAU demonstrate stronger persistence during upward trends. Analysis of multifractality sources using surrogate time series confirms the influence of fat-tailed distributions and temporal linear correlations in most asset pairs, with the exception of WTI, which shows less complex behavior. Overall, the findings underscore the utility of multifractal asymmetric cross-correlation analysis in capturing the intricate dynamics of semiconductor stocks. This approach provides valuable insights for investors and portfolio managers by accounting for the multifaceted and asset-dependent nature of stock behavior under varying market conditions. Full article

Plastic injection molding is a fundamental manufacturing process used in various industries, accounting for approximately 30% of the global plastic product market. A significant challenge of this process lies in the need to employ sophisticated computational techniques to optimize the various phases. This review examines the optimization methodologies in injection molding, with a focus on integrating advanced modeling, surrogate models, and multi-objective optimization techniques to enhance efficiency, quality, and sustainability. Key phases such as plasticizing, filling, packing, cooling, and ejection are analyzed, each presenting unique optimization challenges. The review emphasizes the importance of cooling, which accounts for 50–80% of the cycle time, and examines innovative strategies, such as conformal cooling channels (CCCs), to enhance uniformity and minimize defects. Various computational tools, including Moldex3D and Autodesk Moldflow, are discussed due to their role in process simulation and optimization. Additionally, optimization algorithms such as evolutionary algorithms, simulated annealing, and multi-objective optimization methods are explored. The integration of surrogate models, such as Kriging, response surface methodology, and artificial neural networks, has shown promise in addressing computational cost challenges. Future directions emphasize the need for adaptive machine learning and artificial intelligence techniques to optimize molds in real time, offering more innovative and sustainable manufacturing solutions. This review is a comprehensive guide for researchers and practitioners, bridging theoretical advancements with practical implementation in injection molding optimization. Full article

As autonomous driving technology advances, connected and autonomous vehicles (CAVs) will coexist with human-driven vehicles (HDVs) for an extended period. The deployment of CAVs will alter traffic flow characteristics, making it crucial to investigate their impacts on mixed traffic. This study develops a hybrid control framework that integrates a platoon control strategy based on the “catch-up” mechanism with lane management for CAVs. The impacts of the proposed hybrid control framework on mixed traffic flow are evaluated through a series of macroscopic simulations, focusing on fundamental diagrams, traffic oscillations, and safety. The results illustrate a notable increase in road capacity with the rising market penetration rate (MPR) of CAVs, with significant improvements under the hybrid control framework, particularly at high MPRs. Additionally, traffic oscillations are mitigated, reducing shockwave propagation and enhancing efficiency under the hybrid control framework. Four surrogate safety measures, namely time to collision (TTC), criticality index function (CIF), deceleration rate to avoid a crash (DRAC), and total exposure time (TET), are utilized to evaluate traffic safety. The results indicate that collision risk is significantly reduced at high MPRs. The findings of this study provide valuable insights into the deployment of CAVs, using control strategies to improve mixed traffic flow operations. Full article

The use of dedicated lanes, known as managed lanes (MLs), on freeways is an established traffic management strategy to reduce congestion. Allowing automated vehicles (AVs) in existing MLs or dedicating MLs for AVs, referred to as AVMLs, has been suggested in the literature as a tool to improve traffic operation and safety performance as AVs and driver-operated vehicles (DVs) coexist in a mixed-vehicle environment. This paper focuses on investigating the safety impacts of deploying AVMLs on freeways by repurposing general-purpose lanes (GPLs). Four ML strategies considering different lane positions and access controls were implemented in a traffic microsimulation under different AV market adoption rates (MARs) and traffic demand levels, and trajectories were used to extract rear-end and lane change conflicts. The time-to-collision (TTC) surrogate safety measure was used to identify critical conflicts using a time threshold dependent on the type of following vehicle. Rates of conflicts involving different vehicle types for all ML strategies were compared to the case of heterogeneous traffic. The results indicated that the rates of rear-end conflicts involving the same vehicle type as the lead and following vehicle, namely DV-DV and AV-AV conflicts, increased with ML implementation as more vehicles of the same type traveled in the same lane(s). By comparing the aggregated conflict rates, the design options that were deemed to negatively impact traffic efficiency and capacity were also found to negatively impact traffic safety. However, other ML options were found to be feasible in terms of traffic operation and safety performance, especially at traffic demand levels below capacity. Specifically, one left-side AVML with continuous access was found to have lower or comparable aggregated conflict rates compared to heterogenous traffic at 25% and 50% MARs, and, thus, it is expected to have positive or neutral safety impacts. Full article

Doxycycline is a second-generation tetracycline, marketed in different species for treating infections caused by susceptible bacteria. Little information is available on the pharmacokinetics of doxycycline in lactating goats. The objective of this study was to establish the disposition kinetics of doxycycline after parenteral administration (intravenous and intramuscular) in dairy goats and its elimination in milk. A cross-over model was designed (n = 6). Doxycycline was dosed at 5 mg/kg for intravenous administration and 20 mg/kg for extravascular administrations. Noncompartmental pharmacokinetic methods were used to calculate plasma concentration–time data. The V_z value suggests a moderate distribution of this antibiotic in goats, with a value of 0.85 L/kg. A low bioavailability (F = 45.60%) of doxycycline following an intramuscular injection was observed, with all animals exhibiting signs of lameness. Doxycycline rapidly crossed the blood–milk barrier, but exposure to the antimicrobial and the concentrations reached in milk were lower than those obtained in plasma. Although PK/PD ratios may be low with the pharmacokinetic data obtained with this formulation of doxycycline, at this dose and route of administration, doxycycline after IM administration could be useful for infections by moderate or highly susceptible bacteria in the mammary gland of goats. However, it may be necessary to test different doses of doxycycline or other routes of administration to achieve better surrogate markers and to establish repeated dosing regimens and clinical efficacy. Full article

Background: Understanding the concept and dynamic process of the evolution of professional identity and roles of market access (MA) in the pharmaceutical industry (pharma) is critical to personal, interpersonal, and professional levels of development and impact. Objective: The aim was to carry out a scoping review of the conceptualisation of MA within pharma. Data Sources: BioMed Central, WorldCat.org, and Directory of Open Access Journals were searched from 2003 to 2023. Study Selection: All articles on concepts or definitions and other surrogate terms on MA in pharma were selected. Data Extraction: Keywords generated from an initial cursory literature search on MA in pharma were used in conjunction with AND/OR as search terms. Using the data charting method, key findings were mapped and summarised descriptively. inductive analysis was performed, allowing codes/themes that are relevant to the concept to emerge. Data Synthesis: Arskey and O’Malley’s six-stage framework and the PRISMA extension for scoping reviews extension checklist were used as the review and reporting templates. The databases search yielded 222 results. Following title and abstract screening, a total of 146 papers were screened, and 127 of them were excluded. Full-text review was conducted for 19 papers that were deemed by two reviewers to meet the eligibility criteria. One of the authors arbitrated on disputed papers for inclusion. Only 14 of the included papers were found to meet the criteria for the final analysis. Five conceptual dimensions of MA in pharma were identified as “right products”, “right patient”, “right price”, “right point” (time), and “right place” (setting). Conclusions: Market access in pharma is a process that commences with the development and availability of the right products that are proven to be efficacious and disease/condition-specific (including medications, medical devices, and vaccines); specifically produced for the right patients or end users who will maximise best clinical outcomes and economic value; delivered at the right point in a timely, sustained, and efficient manner, given at the right price (commercially viable or reimbursed price that represents good value); and conducted within the economic, policy, societal, and technological contexts, with the overarching goal of achieving the best patient outcomes and ensuring product profitability. Full article

Limitations of pharmaceutical drugs and biologics for chronic diseases (e.g., medication non-adherence, adverse effects, toxicity, or inadequate efficacy) can be mitigated by mobile medical apps, known as digital therapeutics (DTx). Authorization of adjunct DTx by the US Food and Drug Administration and draft guidelines on “prescription drug use-related software” illustrate opportunities to create drug + digital combination therapies, ultimately leading towards drug–device combination products (DTx has a status of medical devices). Digital interventions (mobile, web-based, virtual reality, and video game applications) demonstrate clinically meaningful benefits for people living with Alzheimer’s disease, dementia, rheumatoid arthritis, cancer, chronic pain, epilepsy, depression, and anxiety. In the respective animal disease models, preclinical studies on environmental enrichment and other non-pharmacological modalities (physical activity, social interactions, learning, and music) as surrogates for DTx “active ingredients” also show improved outcomes. In this narrative review, we discuss how drug + digital combination therapies can impact translational research, drug discovery and development, generic drug repurposing, and gene therapies. Market-driven incentives to create drug–device combination products are illustrated by Humira^® (adalimumab) facing a “patent-cliff” competition with cheaper and more effective biosimilars seamlessly integrated with DTx. In conclusion, pharma and biotech companies, patients, and healthcare professionals will benefit from accelerating integration of digital interventions with pharmacotherapies. Full article

Quetiapine is a second-generation antipsychotic drug available for two and half decades. Due to increased misuse, prescription outside the approved indications, and availability on the black market, it is being encountered in medicolegal autopsies more frequently. For instance, it has been linked to increased mortality rates, most likely due to its adverse effects on the cardiovascular system. Its pharmacokinetic features and significant postmortem redistribution challenge traditional sampling in forensic toxicology. Therefore, a systematic literature review was performed, inclusive of PubMed, the Web of Science—core collection, and the Scopus databases; articles were screened for the terms “quetiapine”, “death”, and “autopsy” to reevaluate each matrix used as a surrogate endpoint in the forensic toxicology of quetiapine-related deaths. Ultimately, this review considers the results of five studies that were well presented (more than two matrices, data available for all analyses, for instance). The highest quetiapine concentrations were usually measured in the liver tissue. As interpreted by their authors, the results of the considered studies showed a strong correlation between some matrices, but, unfortunately, the studies presented models with poor goodness of fit. The distribution of quetiapine in distinct body compartments/tissues showed no statistically significant relationship with the length of the postmortem interval. Furthermore, this study did not confirm the anecdotal correlation of peripheral blood concentrations with skeletal muscle concentrations. Otherwise, there was no consistency regarding selecting an endpoint for analysis. Full article

In the insurance industry, life insurers are required by regulators to meet capital requirements to avoid insolvency caused by, for example, sudden mortality changes due to the COVID-19 pandemic. To prevent any large movements in this required capital, insurance companies are motivated to establish hedging strategies to mitigate the inherent risk exposures they face. Nonetheless, devising and implementing risk mitigation solutions to risk managing capital requirement is frequently impeded by the computational complexities stemming from the extensive simulations required. In this paper, we delve into a simulation quandary concerning the management of solvency capital risk associated with mortality and longevity. More specifically, we introduce a thin-plate regression spline method as a surrogate alternative to the standard nested simulation approach. Using this efficient simulation method, we further investigate hedging strategies that utilize mortality-linked securities coupled with stochastic mortality dynamics. Our simulation results provide a numerical justification to the market-making of mortality-linked securities in the context of mortality and longevity capital risk management. Full article

The global coconut water market is projected to grow in the upcoming years, attributed to its numerous health benefits. However, due to its susceptibility to microbial contamination and the limitations of non-thermal decontamination methods, thermal treatments remain the primary approach to ensure the shelf-life stability and the microbiological safety of the product. In this study, the thermal inactivation of Listeria innocua, a Listeria monocytogenes surrogate, was evaluated in coconut water and in tryptone soy broth (TSB) under both isothermal (50–60 °C) and dynamic conditions (from 30 to 60 °C, with temperature increases of 0.5, 1 and 5 °C/min). Mathematical models were used to analyse the inactivation data. The Geeraerd model effectively described the thermal inactivation of L. innocua in both TSB and coconut water under isothermal conditions, with close agreement between experimental data and model fits. Parameter estimates and analysis revealed that acidified TSB is a suitable surrogate medium for studying the thermal inactivation of L. innocua in coconut water, despite minor differences observed in the shoulder length of inactivation curves, likely attributed to the media composition. The models fitted to the data obtained at isothermal conditions fail to predict L. innocua responses under dynamic conditions. This is attributed to the stress acclimation phenomenon that takes place under dynamic conditions, where bacterial cells adapt to initial sub-lethal treatment stages, leading to increased thermal resistance. Fitting the Bigelow model directly to dynamic data with fixed z-values reveals a three-fold increase in D-values with lower heating rates, supporting the role of stress acclimation. The findings of this study aid in designing pasteurization treatments targeting L. innocua in coconut water and enable the establishment of safe, mild heat treatments for refrigerated, high-quality coconut water. Full article