Planning of school teaching during Covid-19.

Learning and education are two of the biggest world issues of the current pandemic. Unfortunately, it is seen in this work that, due to the length of the incubation period of Covid-19, full opening of schools in the Fall of 2020 seems to be impractical unless the spread of the virus is completely under control in the surrounding region (e.g. with fewer than 5 active cases every million people). In order to support the possibility of some in-person learning, we model the diffusion of the epidemic within each single school by an SEAIR model with an external source of infection and a suitable loss function, and then evaluate sustainable opening plans. It turns out that blended models, with almost periodic alternations of in-class and remote teaching days or weeks, are generally (close to) optimal. In a prototypical example, the optimal strategy prescribes a school opening of 90 days out of 200 with the number of Covid-19 cases among the individuals related to the school increasing by about 67% with respect to no opening, instead of the about 200% increase that would have been a consequence of full opening. As clinical fraction is low in children, these solutions could lead to very few or no symptomatic cases within the school during the whole school year. Using the prevalence of active cases as a proxy for the number of pre- and asymptomatic, we get a preliminary indication for each country of whether either full opening, or blended opening with frequent testing, or no school opening at all, is advisable.

Mortality containment vs. Economics Opening: Optimal policies in a SEIARD model.

We extend the classic approach (SIR) to a SEAIRD model with policy controls. A social planner's objective reflects the trade-off between mortality reduction and GDP, featuring its perception of the value of statistical life (PVSL). We introduce realistic and drastic limitations to the control available to it. Within this setup, we explore the results of various control policies. We notably describe the joint dynamics of infection and economy in different contexts with unique or multiple confinement episodes. Compared to other approaches, our contributions are: (i) to restrict the class of functions accessible to the social planner, and in particular to impose that they remain constant over some fixed periods; (ii) to impose implementation frictions, e.g. a lag in their implementation; (iii) to prove the existence of optimal strategies within this set of possible controls; iv) to exhibit a sudden change in optimal policy as the statistical value of life is raised, from laissez-faire to a sizeable lockdown level, indicating a possible reason for conflicting policy proposals.

A cluster randomized trial to measure the impact on nonsteroidal anti-inflammatory drug and proton pump inhibitor prescribing in Italy of distributing cost-free paracetamol to osteoarthritic patients.

BACKGROUND: Paracetamol is recommended as first-line treatment for pain control in osteoarthritis because it has fewer side effects than do other therapeutic options, including nonsteroidal anti-inflammatory drugs (NSAIDs). Prescribing proton pump inhibitors (PPIs) as gastric bleeding prophylaxis in chronic NSAID users is also common, although not recommended. In Italy, paracetamol is not reimbursed by the National Health System. The aim of this trial was to test whether the availability to osteoarthritis patients of free paracetamol would decrease their use of NSAIDs and, as a secondary objective, whether opioid and PPI consumption would also decrease. METHODS: Eight general practitioners (GPs) (59 patients) were randomized to usual care and 8 (58 patients) to the experimental arm, where prescribed paracetamol was directly distributed for free by the local hospital. After 6 months, paracetamol was also available for free in the control arm. The main outcome was the pre/post difference in average NSAID and PPI consumption. Differences between experimental and control arms in pre/post differences are reported, as registered by the drug prescription information system. RESULTS: Average NSAID consumption decreased non-significantly, from 6.79 to 2.16 defined daily dose (DDD) in the experimental arm and from 3.19 to 2.97 DDD in the control group (p = 0.067). No changes were observed for PPIs (from 11.27 to 14.65 DDD and from 9.74 to 12.58 DDD in experimental and control arms, respectively, p = 0.788) or opioids (from 1.61 to 1.14 DDD and from 1.41 to 1.56 DDD in experimental and control arms, respectively, p = 0.419). When the intervention was extended to the control arm, no decrease in NSAID consumption was observed (from 2.46 to 2.43 DDD, p = 0.521). CONCLUSIONS: Removing small economic barriers had small or no effect on the appropriateness of opioid or PPI prescribing to patients with osteoarthritis; a reduction in NSAID consumption cannot be ruled out. TRIAL REGISTRATION NUMBER: NCT02691754 (Approved February 24, 2016).

Nucleotide Excision Repair and Transcription-coupled DNA Repair Abrogate the Impact of DNA Damage on Transcription.

DNA adducts derived from carcinogenic polycyclic aromatic hydrocarbons like benzo[a]pyrene (B[a]P) and benzo[c]phenanthrene (B[c]Ph) impede replication and transcription, resulting in aberrant cell division and gene expression. Global nucleotide excision repair (NER) and transcription-coupled DNA repair (TCR) are among the DNA repair pathways that evolved to maintain genome integrity by removing DNA damage. The interplay between global NER and TCR in repairing the polycyclic aromatic hydrocarbon-derived DNA adducts (+)-trans-anti-B[a]P-N(6)-dA, which is subject to NER and blocks transcription in vitro, and (+)-trans-anti-B[c]Ph-N(6)-dA, which is a poor substrate for NER but also blocks transcription in vitro, was tested. The results show that both adducts inhibit transcription in human cells that lack both NER and TCR. The (+)-trans-anti-B[a]P-N(6)-dA lesion exhibited no detectable effect on transcription in cells proficient in NER but lacking TCR, indicating that NER can remove the lesion in the absence of TCR, which is consistent with in vitro data. In primary human cells lacking NER, (+)-trans-anti-B[a]P-N(6)-dA exhibited a deleterious effect on transcription that was less severe than in cells lacking both pathways, suggesting that TCR can repair the adduct but not as effectively as global NER. In contrast, (+)-trans-anti-B[c]Ph-N(6)-dA dramatically reduces transcript production in cells proficient in global NER but lacking TCR, indicating that TCR is necessary for the removal of this adduct, which is consistent with in vitro data showing that it is a poor substrate for NER. Hence, both global NER and TCR enhance the recovery of gene expression following DNA damage, and TCR plays an important role in removing DNA damage that is refractory to NER.

The steady state of epidermis: mathematical modeling and numerical simulations.

We consider a model with age and space structure for the epidermis evolution. The model, previously presented and analyzed with respect to the suprabasal epidermis, includes different types of cells (proliferating cells, differentiated cells, corneous cells, and apoptotic cells) moving with the same velocity, under the constraint that the local volume fraction occupied by the cells is constant in space and time. Here, we complete the model proposing a mechanism regulating the cell production in the basal layer and we focus on the stationary case of the problem, i.e. on the case corresponding to the normal status of the skin. A numerical scheme to compute the solution of the model is proposed and its convergence is studied. Simulations are provided for realistic values of the parameters, showing the possibility of reproducing the structure of both "thin" and "thick" epidermis.

The role of stochastic gene switching in determining the pharmacodynamics of certain drugs: basic mechanisms.

In this paper we analyze the impact of the stochastic fluctuation of genes between their ON and OFF states on the pharmacodynamics of a potentially large class of drugs. We focus on basic mechanisms underlying the onset of in vitro experimental dose-response curves, by investigating two elementary molecular circuits. Both circuits consist in the transcription of a gene and in the successive translation into the corresponding protein. Whereas in the first the activation/deactivation rates of the single gene copy are constant, in the second the protein, now a transcription factor, amplifies the deactivation rate, so introducing a negative feedback. The drug is assumed to enhance the elimination of the protein, and in both cases the success of therapy is assured by keeping the level of the given protein under a threshold for a fixed time. Our numerical simulations suggests that the gene switching plays a primary role in determining the sigmoidal shape of dose-response curves. Moreover, the simulations show interesting phenomena related to the magnitude of the average gene switching time and to the drug concentration. In particular, for slow gene switching a significant fraction of cells can respond also in the absence of drug or with drug concentrations insufficient for the response in a deterministic setting. For higher drug concentrations, the non-responding fraction exhibits a maximum at intermediate values of the gene switching rates. For fast gene switching, instead, the stochastic prediction follows the prediction of the deterministic approximation, with all the cells responding or non-responding according to the drug dose.

The pharmacodynamics of the p53-Mdm2 targeting drug Nutlin: the role of gene-switching noise.

In this work we investigate, by means of a computational stochastic model, how tumor cells with wild-type p53 gene respond to the drug Nutlin, an agent that interferes with the Mdm2-mediated p53 regulation. In particular, we show how the stochastic gene-switching controlled by p53 can explain experimental dose-response curves, i.e., the observed inter-cell variability of the cell viability under Nutlin action. The proposed model describes in some detail the regulation network of p53, including the negative feedback loop mediated by Mdm2 and the positive loop mediated by PTEN, as well as the reversible inhibition of Mdm2 caused by Nutlin binding. The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold. We also performed in silico experiments to evaluate the dose-response curve after a single drug dose delivered in mice, or after its fractionated administration. Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses. This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug.

Epidemic dynamics and host immune response: a nested approach.

This paper proposes an approach for building epidemiological models that incorporate the intra-host pathogen-immunity dynamics. The infected population is structured in terms of pathogen load and level of immunity, and the initial infection load may depend on the load of the individual from whom the infection is acquired. In particular, we focus on the case in which the initial inoculum is taken proportional to the load of the infectant. Possible reinfections are disregarded. Such an approach is applied to formulate an epidemic model with isolation in a closed population by introducing a specific intra-host dynamics. A numerical scheme for the solution of model equations is developed, and some numerical results illustrating the role of the initial inoculum, of the isolation threshold and of the pathogen dynamics on the epidemic evolution are presented. From the simulations the distributions of latency, infectivity, and isolation times can be also derived; however the predictions of the present models differ qualitatively from those of traditional SEIHR models with distributed latency, infectivity and isolation periods.

Perception, performance, and detectability of conversational artificial intelligence across 32 university courses.

The emergence of large language models has led to the development of powerful tools such as ChatGPT that can produce text indistinguishable from human-generated work. With the increasing accessibility of such technology, students across the globe may utilize it to help with their school work-a possibility that has sparked ample discussion on the integrity of student evaluation processes in the age of artificial intelligence (AI). To date, it is unclear how such tools perform compared to students on university-level courses across various disciplines. Further, students' perspectives regarding the use of such tools in school work, and educators' perspectives on treating their use as plagiarism, remain unknown. Here, we compare the performance of the state-of-the-art tool, ChatGPT, against that of students on 32 university-level courses. We also assess the degree to which its use can be detected by two classifiers designed specifically for this purpose. Additionally, we conduct a global survey across five countries, as well as a more in-depth survey at the authors' institution, to discern students' and educators' perceptions of ChatGPT's use in school work. We find that ChatGPT's performance is comparable, if not superior, to that of students in a multitude of courses. Moreover, current AI-text classifiers cannot reliably detect ChatGPT's use in school work, due to both their propensity to classify human-written answers as AI-generated, as well as the relative ease with which AI-generated text can be edited to evade detection. Finally, there seems to be an emerging consensus among students to use the tool, and among educators to treat its use as plagiarism. Our findings offer insights that could guide policy discussions addressing the integration of artificial intelligence into educational frameworks.

A new threshold reveals the uncertainty about the effect of school opening on diffusion of Covid-19.

Studies on the effects of school openings or closures during the Covid-19 pandemic seem to reach contrasting conclusions even in similar contexts. We aim at clarifying this controversy. A mathematical analysis of compartmental models with subpopulations has been conducted, starting from the SIR model, and progressively adding features modeling outbreaks or upsurge of variants, lockdowns, and vaccinations. We find that in all cases, the in-school transmission rates only affect the overall course of the pandemic above a certain context dependent threshold. We provide rigorous proofs and computations of the thresdhold through linearization. We then confirm our theoretical findings through simulations and the review of data-driven studies that exhibit an often unnoticed phase transition. Specific implications are: awareness about the threshold could inform choice of data collection, analysis and release, such as in-school transmission rates, and clarify the reason for divergent conclusions in similar studies; schools may remain open at any stage of the Covid-19 pandemic, including variants upsurge, given suitable containment rules; these rules would be extremely strict and hardly sustainable if only adults are vaccinated, making a compelling argument for vaccinating children whenever possible.

An age-structured model of epidermis growth.

We propose a model with age and space structure for the evolution of the supra-basal epidermis. The model includes different types of cells: proliferating cells, differentiated cells, corneous cells, and apoptotic cells. We assume that all cells move with the same velocity and that the local volume fraction, occupied by the cells is constant in space and time. This hypothesis, based on experimental evidence, allows us to determine a constitutive equation for the cell velocity. We focus on the stationary case of the problem, that takes the form of a quasi-linear evolution problem of first order, and we investigate conditions under which there is a solution.

Chemotherapy of vascularised tumours: role of vessel density and the effect of vascular "pruning".

In this work we propose to model chemotherapy taking into account the mutual interaction between tumour growth and the development of tumour vasculature. By adopting a simple model for this interaction, and assuming that the efficacy of a drug can be modulated by the vessel density, we study the constant continuous therapy, the periodic bolus-based therapy, and combined therapy in which a chemotherapic drug is associated with an anti-angiogenic agent. The model allows to represent the vessel-disrupting activity of some standard chemotherapic drugs, and shows, in the case of constant continuous drug administration, the possibility of multiple stable equilibria. The multistability suggests an explanation for some sudden losses of control observed during therapy, and for the beneficial effect of vascular "pruning" exerted by anti-angiogenic agents in combined therapy. Moreover, in case of periodic therapies in which the drug amount administered per unit time is constant ("metronomic" delivery), the model predicts a response, as a function of the bolus frequency, significantly influenced by the extent of the anti-angiogenic activity of the chemotherapic drug and by the dependence of the drug efficacy on the vessel density.

Necrotic core in EMT6/Ro tumour spheroids: Is it caused by an ATP deficit?

Although commonly related to nutrient deprivation, the cause of the formation of the necrotic core in the multicellular tumour spheroids is still a controversial issue. We propose a simple model for the cell ATP production that assumes glucose and lactate as the only fuel substrates, and describes the main reactions occurring in the glycolytic and the oxidative pathways. Under the key assumption that cell death occurs when ATP production falls to a critical level, we formulate a multiscale model that integrates the energy metabolism at the cellular level with the diffusive transport of the metabolites in the spheroid mass. The model has been tested by predicting the measurements of the necrotic radius obtained by Freyer and Sutherland (1986a) in EMT6/Ro spheroids under different concentrations of glucose and oxygen in the culture medium. The results appear to be in agreement with the hypothesis that necrosis is caused by ATP deficit.

Impact of ART-induced viral suppression on the HIV epidemic in Italy.

The present study aims to clarify the role of the fraction of patients under antiretroviral therapy (ART) achieving viral suppression (VS) (i.e. having plasma viral load below the detectability threshold) on the human immunodeficiency virus (HIV) epidemic in Italy. Based on the hypothesis that VS makes the virus untransmittable, we extend a previous model and we develop a time-varying ordinary differential equation model with immigration and treatment, where the naive and non-naive populations of infected are distinguished, and different compartments account for treated subjects virally suppressed and not suppressed. Moreover, naive and non-naive individuals with acquired immune deficiency syndrome (AIDS) are considered separately. Clinical data stored in the nationwide database Antiviral Response Cohort Analysis are used to reconstruct the history of the fraction of virally suppressed patients since highly active ART introduction, as well as to assess some model parameters. Other parameters are set according to the literature and the final model calibration is obtained by fitting epidemic data over the years 2003-2015. Predictions on the evolution of the HIV epidemic up to the end of 2035 are made assuming different future trends of the fraction of virally suppressed patients and different eligibility criteria for treatment. Increasing the VS fraction is found to reduce the incidence, the new cases of AIDS and the deaths from AIDS per year, especially in combination with early ART initiation. The asymptotic properties of a time-invariant formulation of the model are studied, and the existence and global asymptotic stability of a unique positive equilibrium are proved.

A simple model of pathogen-immune dynamics including specific and non-specific immunity.

We present and analyze a model for the dynamics of the interactions between a pathogen and its host's immune response. The model consists of two differential equations, one for pathogen load, the other one for an index of specific immunity. Differently from other simple models in the literature, this model exhibits, according to the hosts' or pathogen's parameter values, or to the initial infection size, a rich repertoire of behaviours: immediate clearing of the pathogen through aspecific immune response; or acute infection followed by clearing of the pathogen through specific immune response; or uncontrolled infections; or acute infection followed by convergence to a stable state of chronic infection; or periodic solutions with intermittent acute infections. The model can also mimic some features of immune response after vaccination. This model could be a basis on which to build epidemic models including immunological features.

A simple model of HIV epidemic in Italy: The role of the antiretroviral treatment.

In the present paper we propose a simple time-varying ODE model to describe the evolution of HIV epidemic in Italy. The model considers a single population of susceptibles, without distinction of high-risk groups within the general population, and accounts for the presence of immigration and emigration, modelling their effects on both the general demography and the dynamics of the infected subpopulations. To represent the intra-host disease progression, the untreated infected population is distributed over four compartments in cascade according to the CD4 counts. A further compartment is added to represent infected people under antiretroviral therapy. The per capita exit rate from treatment, due to voluntary interruption or failure of therapy, is assumed variable with time. The values of the model parameters not reported in the literature are assessed by fitting available epidemiological data over the decade 2003÷2012. Predictions until year 2025 are computed, enlightening the impact on the public health of the early initiation of the antiretroviral therapy. The benefits of this change in the treatment eligibility consist in reducing the HIV incidence rate, the rate of new AIDS cases, and the rate of death from AIDS. Analytical results about properties of the model in its time-invariant form are provided, in particular the global stability of the equilibrium points is established either in the absence and in the presence of infected among immigrants.

Tumour eradication by antiangiogenic therapy: analysis and extensions of the model by Hahnfeldt et al. (1999).

The model proposed by Hahnfeldt et al. (1999) describes the growth of a tumour assuming that tumour growth is strictly controlled by the evolution of the vascular network that supplies oxygen and nutrients to tumour cells. Consequently, it provides a framework to represent the effects of antiangiogenic therapies. In this paper, some possible modifications of that model are proposed, and conditions that guarantee the eradication of the tumour under a regimen of periodic antiangiogenic therapy are derived. The model variants considered assume the potential doubling time of the vasculature to be constant, and subdivide the endothelial cell pool, which is involved in angiogenesis, in resting and proliferating cells allowing for a more detailed description of drug effects.

Cell kinetics in tumour cords studied by a model with variable cell cycle length.

A mathematical model is developed that describes the proliferative behaviour at the stationary state of the cell population within a tumour cord, i.e. in a cylindrical arrangement of tumour cells growing around a blood vessel and surrounded by necrosis. The model, that represents the tumour cord as a continuum, accounts for the migration of cells from the inner to the outer zone of the cord and describes the cell cycle by a sequence of maturity compartments plus a possible quiescent compartment. Cell-to-cell variability of cycle phase transit times and changes in the cell kinetic parameters within the cord, related to changes of the microenvironment, can be represented in the model. The theoretical predictions are compared against literature data of the time course of the labelling index and of the fraction of labelled mitoses in an experimental tumour after pulse labelling with 3H-thymidine. It is shown that the presence of cell migration within the cord can lead to a marked underestimation of the actual changes along cord radius of the kinetics of cell cycle progression.

[Ticlopidine-induced acute cholestatic hepatitis. A case report]. / Epatite acuta colestatica da ticlopidina.

A case of acute cholestatic hepatitis associated with use of antiplatelet agent ticlopidine is reported. Hepatitis developed 3 weeks after the beginning of the drug in a 72 year old man submitted to coronary angioplasty and stent implantation for unstable angina. The close time relationship between the administration of this antiplatelet drug and the acute onset of liver damage, the exclusion of other hepatobiliary disease and the progressive normalisation of biochemical parameters following withdrawal of the drug strongly suggest that ticlopidine was involved in the pathogenesis of this syndrome.