Declarative Logic-Based Pareto-Optimal Agent Decision Making.

There are many applications where an autonomous agent can perform many sets of actions. It must choose one set of actions based on some behavioral constraints on the agent. Past work has used deontic logic to declaratively express such constraints in logic, and developed the concept of a feasible status set (FSS), a set of actions that satisfy these constraints. However, multiple FSSs may exist and an agent needs to choose one in order to act. As there may be many different objective functions to evaluate status sets, we propose the novel concept of Pareto-optimal FSSs or . We show that checking if a status set is a is co-NP-hard. We develop an algorithm to find a and in special cases when the objective functions are monotonic (or anti-monotonic), we further develop more efficient algorithms. Finally, we conduct experiments to show the efficacy of our approach and we discuss possible ways to handle multiple Pareto-optimal Status Sets.

Estimating the potential risk of transmission of arboviruses in the Americas and Europe: a modelling study.

BACKGROUND: Estimates of the spatiotemporal distribution of different mosquito vector species and the associated risk of transmission of arboviruses are key to design adequate policies for preventing local outbreaks and reducing the number of human infections in endemic areas. In this study, we quantified the abundance of Aedes albopictus and Aedes aegypti and the local transmission potential for three arboviral infections at an unprecedented spatiotemporal resolution in areas where no entomological surveillance is available. METHODS: We developed a computational model to quantify the daily abundance of Aedes mosquitoes, leveraging temperature and precipitation records. The model was calibrated on mosquito surveillance data collected in 115 locations in Europe and the Americas between 2007 and 2018. Model estimates were used to quantify the reproduction number of dengue virus, Zika virus, and chikungunya in Europe and the Americas, at a high spatial resolution. FINDINGS: In areas colonised by both Aedes species, A aegypti was estimated to be the main vector for the transmission of dengue virus, Zika virus, and chikungunya, being associated with a higher estimate of R0 when compared with A albopictus. Our estimates highlighted that these arboviruses were endemic in tropical and subtropical countries, with the highest risks of transmission found in central America, Venezuela, Colombia, and central-east Brazil. A non-negligible potential risk of transmission was also estimated for Florida, Texas, and Arizona (USA). The broader ecological niche of A albopictus could contribute to the emergence of chikungunya outbreaks and clusters of dengue autochthonous cases in temperate areas of the Americas, as well as in mediterranean Europe (in particular, in Italy, southern France, and Spain). INTERPRETATION: Our results provide a comprehensive overview of the transmission potential of arboviral diseases in Europe and the Americas, highlighting areas where surveillance and mosquito control capacities should be prioritised. FUNDING: EU and Ministero dell'Università e della Ricerca, Italy (Piano Nazionale di Ripresa e Resilienza Extended Partnership initiative on Emerging Infectious Diseases); EU (Horizon 2020); Ministero dell'Università e della Ricerca, Italy (Progetti di ricerca di Rilevante Interesse Nazionale programme); Brazilian National Council of Science, Technology and Innovation; Ministry of Health, Brazil; and Foundation of Research for Minas Gerais, Brazil.

Contributions of cost-effectiveness analyses (CEA) to influenza vaccination policy for older adults in Europe.

This review describes the importance of economic evaluations and real-world evidence (RWE) for the assessment of enhanced influenza vaccines for older adults in Europe. Individuals ≥65 years of age are at increased risk of severe influenza outcomes and many countries in Europe recommend enhanced vaccines for this population to mitigate immunosenescence. Some National Immunization Technical Advisory Groups (NITAGs) may preferentially recommend a specific enhanced vaccine, necessitating comparative economic evaluation and estimation of relative vaccine effectiveness between enhanced vaccine options in the absence of direct head-to-head efficacy data. Distinct approaches to economic modeling and cost-effectiveness analysis (CEA) guide national vaccination policies in Europe, including how underlying data, such as RWE, are used in these models. RWE is an important evidence source for input into CEA models based on disease factors (e.g., antigenic shift and seasonal variation) and practical factors (e.g., limitations of performing multiple randomized clinical trials to capture seasonal variation; the need to obtain relevant patient-oriented, real-world endpoints, such as hospitalizations). CEA is considered crucial to vaccine assessment among certain countries in Europe, but further harmonization of economic evaluations, including the use of RWE, across NITAGs in Europe may be of benefit, alongside standardized approaches for vaccine appraisal. In the future, more countries may use RWE as an input in CEA models to support NITAG recommendations for enhanced influenza vaccines in older populations, especially considering the value of RWE for the assessment of influenza epidemiology and vaccine effectiveness as stated by the World Health Organization, and the availability of a broad RWE base for certain enhanced vaccines.

Real-World Evidence in Cost-Effectiveness Analysis of Enhanced Influenza Vaccines in Adults ≥ 65 Years of Age: Literature Review and Expert Opinion.

Influenza vaccination can benefit most populations, including adults ≥ 65 years of age, who are at greater risk of influenza-related complications. In many countries, enhanced vaccines, such as adjuvanted, high-dose, and recombinant trivalent/quadrivalent influenza vaccines (aTIV/aQIV, HD-TIV/HD-QIV, and QIVr, respectively), are recommended in older populations to provide higher immunogenicity and increased relative vaccine efficacy/effectiveness (rVE) than standard-dose vaccines. This review explores how efficacy and effectiveness data from randomized controlled trials and real-world evidence (RWE) are used in economic evaluations. Findings from published cost-effectiveness analyses (CEA) on enhanced influenza vaccines for older adults are summarized, and the assumptions and approaches used in these CEA are assessed alongside discussion of the importance of RWE in CEA. Results from many CEA showed that adjuvanted and high-dose enhanced vaccines were cost-effective compared with standard vaccines, and that differences in rVE estimates and acquisition price may drive differences in cost-effectiveness estimates between enhanced vaccines. Overall, RWE and CEA provide clinical and economic rationale for enhanced vaccine use in people ≥ 65 years of age, an at-risk population with substantial burden of disease. Countries that consider RWE when making vaccine recommendations have preferentially recommended aTIV/aQIV, as well as HD-TIV/HD-QIV and QIVr, to protect older individuals.

Modelling the West Nile virus force of infection in the European human population.

West Nile virus (WNV) is among the most recent emerging mosquito-borne pathogens in Europe where each year hundreds of human cases are recorded. We developed a relatively simple technique to model the WNV force of infection (FOI) in the human population to assess its dependence on environmental and human demographic factors. To this aim, we collated WNV human case-based data reported to the European Surveillance System from 15 European Countries during the period 2010-2021. We modelled the regional WNV FOI for each year through normal distributions and calibrated the constituent parameters, namely average (peak timing), variance and overall intensity, to observed cases. Finally, we investigated through regression models how these parameters are associated to a set of climatic, environmental and human demographic covariates. Our modelling approach shows good agreement between expected and observed epidemiological curves. We found that FOI magnitude is positively associated with spring temperature and larger in more anthropogenic semi-natural areas, while FOI peak timing is negatively related to summer temperature. Unsurprisingly, FOI is estimated to be greater in regions with a larger fraction of elderly people, who are more likely to contract severe infections. Our results confirm that temperature plays a key role in shaping WNV transmission in Europe and provide some interesting hints on how human presence and demography might affect WNV burden. This simple yet reliable approach could be easily adopted for early warning and to address epidemiological investigations of other vector-borne diseases, especially where eco-epidemiological data are scarce.

An Economic Evaluation of the Adjuvanted Quadrivalent Influenza Vaccine Compared with Standard-Dose Quadrivalent Influenza Vaccine in the Spanish Older Adult Population.

Standard-dose quadrivalent influenza vaccines (QIV) are designed to provide protection against all four influenza strains. Adjuvanted QIV (aQIV), indicated for individuals aged 65+ years, combines MF59® adjuvant (an oil-in-water emulsion of squalene oil) with a standard dose of antigen, and is designed to produce stronger and longer immune response, especially in the elderly where immunosenescence reduces vaccine effectiveness. This study evaluated the cost-effectiveness of aQIV vs. egg-based standard-dose QIV (QIVe) in the elderly population, from the payer and societal perspective in Spain. A dynamic transmission model, which accounts for herd protection, was used to predict the number of medically attended infections in Spain. A decision tree structure was used to forecast influenza-related costs and benefits. Influenza-related probabilities of outpatient visit, hospitalization, work absenteeism, mortality, and associated utilities and costs were extracted from Spanish and European published literature. Relative vaccine effectiveness (rVE) was sourced from two different meta-analyses: the first meta-analysis was informed by laboratory-confirmed influenza studies only, resulting in a rVE = 34.6% (CI95% 2-66%) in favor of aQIV; the second meta-analysis included real world evidence influenza-related medical encounters outcomes, resulting in a rVE = 13.9% (CI95% 4.2-23.5%) in benefit of aQIV. All costs were expressed in 2021 euros. Results indicate that replacing QIVe with aQIV in the Spanish elderly population would prevent on average 43,664 influenza complicated cases, 1111 hospitalizations, and 569 deaths (with a rVE = 34.6%) or 19,104 influenza complicated cases, 486 hospitalizations, and 252 deaths (with a rVE = 13.9%). When the rVE of aQIV vs. QIVe is 34.6%, the incremental cost per quality adjusted life years (QALY) gained was €2240 from the payer; from the societal perspective, aQIV was cost saving compared with QIVe. If the rVE was 13.9%, the incremental cost per QALY was €6694 and €3936 from the payer and societal perspective, respectively. Sensitivity analyses validated the robustness of these findings. Results indicate that replacing QIVe with aQIV in the Spanish elderly population is a cost-effective strategy for the Spanish healthcare system.

New Development in Understanding Drug-Polymer Interactions in Pharmaceutical Amorphous Solid Dispersions from Solid-State Nuclear Magnetic Resonance.

Pharmaceutical amorphous solid dispersions (ASDs) represent a widely used technology to increase the bioavailability of active pharmaceutical ingredients (APIs). ASDs are based on an amorphous API dispersed in a polymer, and their stability is driven by the presence of strong intermolecular interactions between these two species (e.g., hydrogen bond, electrostatic interactions, etc.). The understanding of these interactions at the atomic level is therefore crucial, and solid-state nuclear magnetic resonance (NMR) has demonstrated itself as a very powerful technique for probing API-polymer interactions. Other reviews have also reported exciting approaches to study the structures and dynamic properties of ASDs and largely focused on the study of API-polymer miscibility and on the identification of API-polymer interactions. Considering the increased use of NMR in the field, the aim of this Review is to specifically highlight recent experimental strategies used to identify API-polymer interactions and report promising recent examples using one-dimensional (1D) and two-dimensional (2D) experiments by exploiting the following emerging approaches of very-high magnetic field and ultrafast magic angle spinning (MAS). A range of different ASDs spanning APIs and polymers with varied structural motifs is targeted to illustrate new ways to understand the mechanism of stability of ASDs to enable the design of new dispersions.

Evolutionary dynamics in an SI epidemic model with phenotype-structured susceptible compartment.

We present an SI epidemic model whereby a continuous structuring variable captures variability in proliferative potential and resistance to infection among susceptible individuals. The occurrence of heritable, spontaneous changes in these phenotypic characteristics and the presence of a fitness trade-off between resistance to infection and proliferative potential are explicitly incorporated into the model. The model comprises an ordinary differential equation for the number of infected individuals that is coupled with a partial integrodifferential equation for the population density function of susceptible individuals through an integral term. The expression for the basic reproduction number [Formula: see text] is derived, the disease-free equilibrium and endemic equilibrium of the model are characterised and a threshold theorem involving [Formula: see text] is proved. Analytical results are integrated with the results of numerical simulations of a calibrated version of the model based on the results of artificial selection experiments in a host-parasite system. The results of our mathematical study disentangle the impact of different evolutionary parameters on the spread of infectious diseases and the consequent phenotypic adaption of susceptible individuals. In particular, these results provide a theoretical basis for the observation that infectious diseases exerting stronger selective pressures on susceptible individuals and being characterised by higher infection rates are more likely to spread. Moreover, our results indicate that heritable, spontaneous phenotypic changes in proliferative potential and resistance to infection can either promote or prevent the spread of infectious diseases depending on the strength of selection acting on susceptible individuals prior to infection. Finally, we demonstrate that, when an endemic equilibrium is established, higher levels of resistance to infection and lower degrees of phenotypic heterogeneity among susceptible individuals are to be expected in the presence of infections which are characterised by lower rates of death and exert stronger selective pressures.

Li+ Dynamics of Liquid Electrolytes Nanoconfined in Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) are excellent platforms to design hybrid electrolytes for Li batteries with liquid-like transport and stability against lithium dendrites. We report on Li+ dynamics in quasi-solid electrolytes consisting in Mg-MOF-74 soaked with LiClO4-propylene carbonate (PC) and LiClO4-ethylene carbonate (EC)/dimethyl carbonate (DMC) solutions by combining studies of ion conductivity, nuclear magnetic resonance (NMR) characterization, and spin relaxometry. We investigate nanoconfinement of liquid inside MOFs to characterize the adsorption/solvation mechanism at the basis of Li+ migration in these materials. NMR supports that the liquid is nanoconfined in framework micropores, strongly interacting with their walls and that the nature of the solvent affects Li+ migration in MOFs. Contrary to the "free'' liquid electrolytes, faster ion dynamics and higher Li+ mobility take place in LiClO4-PC electrolytes when nanoconfined in MOFs demonstrating superionic conductor behavior (conductivity σrt > 0.1 mS cm-1, transport number tLi+ > 0.7). Such properties, including a more stable Li electrodeposition, make MOF-hybrid electrolytes promising for high-power and safer lithium-ion batteries.

Modelling Immune Memory Development.

The cellular adaptive immune response to influenza has been analyzed through several recent mathematical models. In particular, Zarnitsyna et al. (Front Immunol 7:1-9, 2016) show how central memory CD8+ T cells reach a plateau after repeated infections, and analyze their role in the immune response to further challenges. In this paper, we further investigate the theoretical features of that model by extracting from the infection dynamics a discrete map that describes the build-up of memory cells. Furthermore, we show how the model by Zarnitsyna et al. (Front Immunol 7:1-9, 2016) can be viewed as a fast-scale approximation of a model allowing for recruitment of target epithelial cells. Finally, we analyze which components of the model are essential to understand the progressive build-up of immune memory. This is performed through the analysis of simplified versions of the model that include some components only of immune response. The analysis performed may also provide a theoretical framework for understanding the conditions under which two-dose vaccination strategies can be helpful.

A geometric analysis of the SIRS epidemiological model on a homogeneous network.

We study a fast-slow version of an SIRS epidemiological model on homogeneous graphs, obtained through the application of the moment closure method. We use GSPT to study the model, taking into account that the infection period is much shorter than the average duration of immunity. We show that the dynamics occurs through a sequence of fast and slow flows, that can be described through 2-dimensional maps that, under some assumptions, can be approximated as 1-dimensional maps. Using this method, together with numerical bifurcation tools, we show that the model can give rise to periodic solutions, differently from the corresponding model based on homogeneous mixing.

Drug-Polymer Interactions in Acetaminophen/Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy.

The bioavailability of insoluble crystalline active pharmaceutical ingredients (APIs) can be enhanced by formulation as amorphous solid dispersions (ASDs). One of the key factors of ASD stabilization is the formation of drug-polymer interactions at the molecular level. Here, we used a range of multidimensional and multinuclear nuclear magnetic resonance (NMR) experiments to identify these interactions in amorphous acetaminophen (paracetamol)/hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) ASDs at various drug loadings. At low drug loading (<20 wt %), we showed that 1H-13C through-space heteronuclear correlation experiments identify proximity between aromatic protons in acetaminophen with cellulose backbone protons in HPMC-AS. We also show that 14N-1H heteronuclear multiple quantum coherence (HMQC) experiments are a powerful approach in probing spatial interactions in amorphous materials and establish the presence of hydrogen bonds (H-bond) between the amide nitrogen of acetaminophen with the cellulose ring methyl protons in these ASDs. In contrast, at higher drug loading (40 wt %), no acetaminophen/HPMC-AS spatial proximity was identified and domains of recrystallization of amorphous acetaminophen into its crystalline form I, the most thermodynamically stable polymorph, and form II are identified. These results provide atomic scale understanding of the interactions in the acetaminophen/HPMC-AS ASD occurring via H-bond interactions.

Melting of hybrid organic-inorganic perovskites.

Several organic-inorganic hybrid materials from the metal-organic framework (MOF) family have been shown to form stable liquids at high temperatures. Quenching then results in the formation of melt-quenched MOF glasses that retain the three-dimensional coordination bonding of the crystalline phase. These hybrid glasses have intriguing properties and could find practical applications, yet the melt-quench phenomenon has so far remained limited to a few MOF structures. Here we turn to hybrid organic-inorganic perovskites-which occupy a prominent position within materials chemistry owing to their functional properties such as ion transport, photoconductivity, ferroelectricity and multiferroicity-and show that a series of dicyanamide-based hybrid organic-inorganic perovskites undergo melting. Our combined experimental-computational approach demonstrates that, on quenching, they form glasses that largely retain their solid-state inorganic-organic connectivity. The resulting materials show very low thermal conductivities (~0.2 W m-1 K-1), moderate electrical conductivities (10-3-10-5 S m-1) and polymer-like thermomechanical properties.

A Model-Based Framework to Identify Optimal Administration Protocols for Immunotherapies in Castration-Resistance Prostate Cancer.

Prostate cancer (PCa) is one of the most frequent cancer in male population. Androgen deprivation therapy is the first-line strategy for the metastatic stage of the disease, but, inevitably, PCa develops resistance to castration (CRPC), becoming incurable. In recent years, clinical trials are testing the efficacy of anti-CTLA4 on CRPC. However, this tumor seems to be resistant to immunotherapies that are very effective in other types of cancers, and, so far, only the dendritic cell vaccine sipuleucel-T has been approved. In this work, we employ a mathematical model of CRPC to determine the optimal administration protocol of ipilimumab, a particular anti-CTLA4, as single treatment or in combination with the sipuleucel-T, by considering both the effect on tumor population and the drug toxicity. To this end, we first introduce a dose-depending function of toxicity, estimated from experimental data, then we define two different optimization problems. We show the results obtained by imposing different constraints, and how these change by varying drug efficacy. Our results suggest administration of high-doses for a brief period, which is predicted to be more efficient than solutions with prolonged low-doses. The model also highlights a synergy between ipilimumab and sipuleucel-T, which leads to a better tumor control with lower doses of ipilimumab. Finally, tumor eradication is also conceivable, but it depends on patient-specific parameters.

Spring temperature shapes West Nile virus transmission in Europe.

West Nile Virus (WNV) is now endemic in many European countries, causing hundreds of human cases every year, with a high spatial and temporal heterogeneity. Previous studies have suggested that spring temperature might play a key role at shaping WNV transmission. Specifically, warmer temperatures in April-May might amplify WNV circulation, thus increasing the risk for human transmission later in the year. To test this hypothesis, we collated publicly available data on the number of human infections recorded in Europe between 2011 and 2019. We then applied generalized linear models to quantify the relationship between human cases and spring temperature, considering both average conditions (over years 2003-2010) and deviations from the average for subsequent years (2011-2019). We found a significant positive association both spatial (average conditions) and temporal (deviations). The former indicates that WNV circulation is higher in usually warmer regions while the latter implies a predictive value of spring conditions over the coming season. We also found a positive association with WNV detection during the previous year, which can be interpreted as an indication of the reliability of the surveillance system but also of WNV overwintering capacity. Weather anomalies at the beginning of the mosquito breeding season might act as an early warning signal for public health authorities, enabling them to strengthen in advance ongoing surveillance and prevention strategies.

Modeling the effect of immunotherapies on human castration-resistant prostate cancer.

In this paper we analyze the potential effect of immunotherapies on castration-resistant form of human Prostate Cancer (PCa). In particular, we examine the potential effect of the dendritic vaccine sipuleucel-T, the only currently available immunotherapy option for advanced PCa, and of ipilimumab, a drug targeting the Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), exposed on the CTLs membrane, currently under Phase II clinical trial. The model, building on the one by Rutter and Kuang, includes different types of immune cells and interactions and is parameterized on available data. Our results show that the vaccine has only a very limited effect on PCa, while repeated treatments with ipilimumab appear potentially capable of controlling and even eradicating an androgen-independent prostate cancer. From a mathematical analysis of a simplified model, it seems likely that, under continuous administration of ipilimumab, the system lies in a bistable situation where both the no-tumor equilibrium and the high-tumor equilibrium are attractive. The schedule of periodic treatments could then determine the outcome, and mathematical models could help determine an optimal schedule.

A quantitative comparison of West Nile virus incidence from 2013 to 2018 in Emilia-Romagna, Italy.

BACKGROUND: West Nile virus (WNV) transmission was much greater in 2018 than in previous seasons in Europe. Focusing on Emilia-Romagna region (northern Italy), we analyzed detailed entomological and epidemiological data collected in 2013-2018 to quantitatively assess environmental drivers of transmission and explore hypotheses to better understand why the 2018 epidemiological season was substantially different than the previous seasons. In particular, in 2018 WNV was detected at least two weeks before the observed circulation in 2013-2017 and in a larger number of mosquito pools. Transmission resulted in 100 neuroinvasive human cases in the region, more than the total number of cases recorded between 2013 and 2017. METHODOLOGY: We used temperature-driven mathematical models calibrated through a Bayesian approach to simulate mosquito population dynamics and WNV infection rates in the avian population. We then estimated the human transmission risk as the probability, for a person living in the study area, of being bitten by an infectious mosquito in a given week. Finally, we translated such risk into reported WNV human infections. PRINCIPAL FINDINGS: The estimated prevalence of WNV in the mosquito and avian populations were significantly higher in 2018 with respect to 2013-2017 seasons, especially in the eastern part of the region. Furthermore, peak avian prevalence was estimated to have occurred earlier, corresponding to a steeper decline towards the end of summer. The high mosquito prevalence resulted in a much greater predicted risk for human transmission in 2018, which was estimated to be up to eight times higher than previous seasons. We hypothesized, on the basis of our modelling results, that such greater WNV circulation might be partially explained by exceptionally high spring temperatures, which have likely helped to amplify WNV transmission at the beginning of the 2018 season.