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Chemical reaction networks are powerful tools for modeling cell signaling and its disruptions in diseases like cancer. Realistic chemical reaction networks involve hundreds of proteins and reactions, resulting in a model depending on a consistently large number of kinetic parameters. Since finely calibrating all the parameters would require an unrealistic amount of data, proper sensitivity analysis is required to identify a subset of parameters for which fine tuning is needed and thus provide a fundamental tool for the qualitative analysis of the network. We present a multidisciplinary approach for computing a set of synthetic sensitivity indices. These indices rank the kinetic parameters, based on the impact that errors in their values would have on the protein concentration profile at equilibrium. Our tests on a chemical reaction network devised for colorectal cells demonstrate the effectiveness of the considered sensitivity indices in different scenarios including in-silico drug dosage and novel therapeutic target discovery. The Matlab code for computing the synthetic sensitivity indices and the data concerning the network for colorectal cells are available at https://github.com/theMIDAgroup/CRN_sensitivity., (© 2024. The Author(s).)

Source localization from M/EEG data is a fundamental step in many analysis pipelines, including those aiming at clinical applications such as the pre-surgical evaluation in epilepsy. Among the many available source localization algorithms, SESAME (SEquential SemiAnalytic Montecarlo Estimator) is a Bayesian method that distinguishes itself for several good reasons: it is highly accurate in localizing focal sources with comparably little sensitivity to input parameters; it allows the quantification of the uncertainty of the reconstructed source(s); it accepts user-defined a priori high- and low-probability search regions in input; it can localize the generators of neural oscillations in the frequency domain. Both a Python and a MATLAB implementation of SESAME are available as open-source packages under the name of SESAMEEG and are well integrated with the main software packages used by the M/EEG community; moreover, the algorithm is part of the commercial software BESA Research (from version 7.0 onwards). While SESAMEEG is arguably simpler to use than other source modeling methods, it has a much richer output that deserves to be described thoroughly. In this article, after a gentle mathematical introduction to the algorithm, we provide a complete description of the available output and show several use cases on experimental M/EEG data., Competing Interests: GL was employed by Bayesian Estimation for Engineering Solutions srl. HB was employed by BESA GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Luria, Viani, Pascarella, Bornfleth, Sommariva and Sorrentino.)

The accurate characterization of cortical functional connectivity from Magnetoencephalography (MEG) data remains a challenging problem due to the subjective nature of the analysis, which requires several decisions at each step of the analysis pipeline, such as the choice of a source estimation algorithm, a connectivity metric and a cortical parcellation, to name but a few. Recent studies have emphasized the importance of selecting the regularization parameter in minimum norm estimates with caution, as variations in its value can result in significant differences in connectivity estimates. In particular, the amount of regularization that is optimal for MEG source estimation can actually be suboptimal for coherence-based MEG connectivity analysis. In this study, we expand upon previous work by examining a broader range of commonly used connectivity metrics, including the imaginary part of coherence, corrected imaginary part of Phase Locking Value, and weighted Phase Lag Index, within a larger and more realistic simulation scenario. Our results show that the best estimate of connectivity is achieved using a regularization parameter that is 1 or 2 orders of magnitude smaller than the one that yields the best source estimation. This remarkable difference may imply that previous work assessing source-space connectivity using minimum-norm may have benefited from using less regularization, as this may have helped reduce false positives. Importantly, we provide the code for MEG data simulation and analysis, offering the research community a valuable open source tool for informed selections of the regularization parameter when using minimum-norm for source space connectivity analyses., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Magnetoencephalography and electroencephalography (M/EEG) seed-based connectivity analysis requires the extraction of measures from regions of interest (ROI). M/EEG ROI-derived source activity can be treated in different ways. It is possible, for instance, to average each ROI's time series prior to calculating connectivity measures. Alternatively, one can compute connectivity maps for each element of the ROI prior to dimensionality reduction to obtain a single map. The impact of these different strategies on connectivity results is still unclear. Here, we address this question within a large MEG resting state cohort (N=113) and within simulated data. We consider 68 ROIs (Desikan-Kiliany atlas), two measures of connectivity (phase locking value-PLV, and its imaginary counterpart- ciPLV), and three frequency bands (theta 4-8 Hz, alpha 9-12 Hz, beta 15-30 Hz). We compare four extraction methods: (i) mean, or (ii) PCA of the activity within the seed or ROI before computing connectivity, map of the (iii) average, or (iv) maximum connectivity after computing connectivity for each element of the seed. Hierarchical clustering is then applied to compare connectivity outputs across multiple strategies, followed by direct contrasts across extraction methods. Finally, the results are validated by using a set of realistic simulations. We show that ROI-based connectivity maps vary remarkably across strategies in terms of connectivity magnitude and spatial distribution. Dimensionality reduction procedures conducted after computing connectivity are more similar to each-other, while PCA before approach is the most dissimilar to other approaches. Although differences across methods are consistent across frequency bands, they are influenced by the connectivity metric and ROI size. Greater differences were observed for ciPLV than PLV, and in larger ROIs. Realistic simulations confirmed that after aggregation procedures are generally more accurate but have lower specificity (higher rate of false positive connections). Though computationally demanding, after dimensionality reduction strategies should be preferred when higher sensitivity is desired. Given the remarkable differences across aggregation procedures, caution is warranted in comparing results across studies applying different methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2023. Published by Elsevier Inc.)

Background: In 2021, twenty out of twenty-one countries in the Eastern and Southern Africa (ESA) region introduced COVID-19 vaccines. With variable willingness to uptake vaccines across countries, the aim of the present study was to better understand factors that impact behavioral and social drivers of vaccination (BeSD). Using the theory-based "increasing vaccination model", the drivers Thinking & Feeling, Social Processes, Motivation, and Practical Issues were adapted to the COVID-19 context and utilized in a cross-country assessment., Methods: Data was collected on 27.240 health workers in Kenya, Malawi, Mozambique, South Africa and South Sudan. This was done by administering a survey of seven target questions via the UNICEF Internet of Good Things (IoGT) online platform between February and August 2021., Results: Findings showed a gap between perceived importance and trust in vaccines: Most health workers thought Covid-19 vaccination was very important for their health, while less than 30% trusted it very much. The pro-vaccination social and work norm was not well established since almost 66% of all respondents would take the vaccine if recommended to them, but only 49% thought most adults would, and only 48% thought their co-workers would. Access was highlighted as a crucial barrier, with less than a quarter reporting that accessing vaccination services for themselves would be very easy. Women exhibited slightly lower scores than men across the board. When testing the associations between drivers in Kenya and South Africa, it appears that when target interventions are developed for specific age groups, social norms become the main drivers of intention to get vaccinated., Conclusions: The present study revealed various key relations with demographic variables that would help immunization programmes and implementing partners to develop targeted interventions. First, there is a serious gap between perceived importance of COVID-19 vaccines and how much trust people in them. Second, problems with access are still rather serious and solving this would strongly benefit those who demand a vaccine, Third, the role of social norms is the most important predictor of willingness when considering age differences., (© 2023. The Author(s).)

Background: During the COVID-19 pandemic, social listening programs across digital channels have become an integral part of health preparedness and response planning, allowing to capture and address questions, information needs, and misinformation shared by users. This study identifies key social listening trends around COVID-19 vaccines in Eastern and Southern Africa and analyses how online conversations about this issue evolved over time., Methods: A taxonomy developed and refined in collaboration with social and behaviour change teams was used to filter online conversations into nine subtopic categories. The taxonomy was applied to online content tracked in 21 countries in Eastern and Southern Africa over the period December 1, 2020-December 31, 2021. Metrics captured included volume of posts or articles and related user engagement. Qualitative analysis of content was conducted to identify key concerns, information voids and misinformation., Results: Over 300,000 articles and posts about COVID-19 vaccines shared by users or outlets geolocated in the region were analysed. These results generated over 14 million engagements on social media and digital platforms. The analysis shows how conversations about access and availability of vaccines represented the largest share of engagement over the course of the period. Conversations about vaccine effectiveness and safety represented the second and third largest share of engagement, with peaks observed in August and November 2021. Online interest in childhood vaccination increased over time as vaccine eligibility criteria expanded in some countries in the region. Conversations mentioning mandates and certificates peaked in the last quarter of 2021, as governments as private sector entities expanded vaccine requirements., Conclusions: Findings from this study show the importance of monitoring conversation trends over time and adjust social listening data collection systems to include emerging topics. The study also points to the need to consider concerns, information voids and misinformation around effectiveness and safety of vaccines in the context of overall concern for vaccine availability and access in Eastern and Southern Africa. This is fundamental to inform social and behaviour change strategies that promote vaccine demand effectively, without increasing public frustration over vaccine availability challenges and downplaying concerns around vaccine equity., (© 2023. The Author(s).)

The Anomalous Long Term Effects in Astronauts (ALTEA) project originally aimed at disentangling the mechanisms behind astronauts' perception of light flashes. To this end, an experimental apparatus was set up in order to concurrently measure the tracks of cosmic radiation particles in the astronauts' head and the electroencephalographic (EEG) signals generated by their brain. So far, the ALTEA data set has never been analyzed with the broader intent to study possible interference between cosmic radiation and the brain, regardless of light flashes. The aim of this work is to define a pipeline to systematically pre-process the ALTEA EEG data. Compared to the analysis of standard EEG recording, this task is made more difficult by the presence of unconventional artifacts due to the extreme recording conditions that, in particular, require the EEG cap to be positioned next to another noisy electronic device, namely the particle detectors. Here we show how standard tools for the analysis of EEG data can be tuned to deal with these unconventional artifacts. After pre-processing the available data we were able to elucidate a shift of the center frequency of the α rhythm induced by visual stimulation, thus proving the effectiveness of the implemented pipeline. This work represents the first study presenting results of signal processing of ALTEA EEG time series. Further, it is the starting point of a future work aimed at analyzing the interaction between EEG and cosmic radiation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Committee on Space Research (COSPAR). Published by Elsevier B.V. All rights reserved.)

A classic approach to estimate individual theta-to-alpha transition frequency (TF) requires two electroencephalographic (EEG) recordings, one acquired in a resting state condition and one showing alpha desynchronisation due, for example, to task execution. This translates into long recording sessions that may be cumbersome in studies involving patients. Moreover, an incomplete desynchronisation of the alpha rhythm may compromise TF estimates. Here we present transfreq, a publicly available Python library that allows TF computation from resting state data by clustering the spectral profiles associated to the EEG channels based on their content in alpha and theta bands. A detailed overview of transfreq core algorithm and software architecture is provided. Its effectiveness and robustness across different experimental setups are demonstrated on a publicly available EEG data set and on in-house recordings, including scenarios where the classic approach fails to estimate TF. We conclude with a proof of concept of the predictive power of transfreq TF as a clinical marker. Specifically, we present a scenario where transfreq TF shows a stronger correlation with the mini mental state examination score than other widely used EEG features, including individual alpha peak and median/mean frequency. The documentation of transfreq and the codes for reproducing the analysis of the article with the open-source data set are available online at https://elisabettavallarino.github.io/transfreq/. Motivated by the results showed in this article, we believe our method will provide a robust tool for discovering markers of neurodegenerative diseases., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICI) directed against programmed death protein 1 (PD-1) and its ligand (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA-4). In spite of these improvements, some patients do not achieve any benefit from ICI, and inevitably develop resistance to therapy over time. Tumor microenvironment (TME) might influence response to immunotherapy due to its prominent role in the multiple interactions between neoplastic cells and the immune system. Studies investigating lung cancer from the perspective of TME pointed out a complex scenario where tumor angiogenesis, soluble factors, immune suppressive/regulatory elements and cells composing TME itself participate to tumor growth. In this review, we point out the current state of knowledge involving the relationship between tumor cells and the components of TME in NSCLC as well as their interactions with immunotherapy providing an update on novel predictors of benefit from currently employed ICI or new therapeutic targets of investigational agents. In first place, increasing evidence suggests that TME might represent a promising biomarker of sensitivity to ICI, based on the presence of immune-modulating cells, such as Treg, myeloid derived suppressor cells, and tumor associated macrophages, which are known to induce an immunosuppressive environment, poorly responsive to ICI. Consequently, multiple clinical studies have been designed to influence TME towards a pro-immunogenic state and subsequently improve the activity of ICI. Currently, the mostly employed approach relies on the association of "classic" ICI targeting PD-1/PD-L1 and novel agents directed on molecules, such as LAG-3 and TIM-3. To date, some trials have already shown promising results, while a multitude of prospective studies are ongoing, and their results might significantly influence the future approach to cancer immunotherapy., Competing Interests: CG declares honoraria from Astra Zeneca, Bristol-Myers-Squibb, Boehringer-Ingelheim, Merck-Sharp-Dohme, Roche, Takeda. CD declares honoraria from Astra Zeneca, Bristol-Myers-Squibb, Merck-Sharp-Dohme, Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Genova, Dellepiane, Carrega, Sommariva, Ferlazzo, Pronzato, Gangemi, Filaci, Coco and Croce.)

Colorectal cancer (CRC) is one of the most deadly and commonly diagnosed tumors worldwide. Several genes are involved in its development and progression. The most frequent mutations concern APC, KRAS, SMAD4, and TP53 genes, suggesting that CRC relies on the concomitant alteration of the related pathways. However, with classic molecular approaches, it is not easy to simultaneously analyze the interconnections between these pathways. To overcome this limitation, recently these pathways have been included in a huge chemical reaction network (CRN) describing how information sensed from the environment by growth factors is processed by healthy colorectal cells. Starting from this CRN, we propose a computational model which simulates the effects induced by single or multiple concurrent mutations on the global signaling network. The model has been tested in three scenarios. First, we have quantified the changes induced on the concentration of the proteins of the network by a mutation in APC, KRAS, SMAD4, or TP53. Second, we have computed the changes in the concentration of p53 induced by up to two concurrent mutations affecting proteins upstreams in the network. Third, we have considered a mutated cell affected by a gain of function of KRAS, and we have simulated the action of Dabrafenib, showing that the proposed model can be used to determine the most effective amount of drug to be delivered to the cell. In general, the proposed approach displays several advantages, in that it allows to quantify the alteration in the concentration of the proteins resulting from a single or multiple given mutations. Moreover, simulations of the global signaling network of CRC may be used to identify new therapeutic targets, or to disclose unexpected interactions between the involved pathways., (© 2021. The Author(s).)

Compartmental analysis is the mathematical framework for the modelling of tracer kinetics in dynamical Positron Emission Tomography. This paper provides a review of how compartmental models are constructed and numerically optimized. Specific focus is given on the identifiability and sensitivity issues and on the impact of complex physiological conditions on the mathematical properties of the models.

Lead (Pb) exposure through water contamination is an important issue at the intersection of public health and water, sanitation, and hygiene (WASH). Behavior-change programs designed to address this pressing problem rarely take a behavioral-science-informed approach, nor do they consider the role of intermediate players who often influence and support behavior change. Social marketing segments the population and focuses on the consumer/user throughout program development and implementation. To illustrate the social marketing process, this cross-sectional, qualitative design study investigates the use of Pb in the construction and maintenance of household pitcher pumps for potable water in Madagascar. A sample of 18 technicians were interviewed on their current practices, motivators, barriers, and communication channels for knowledge exchange. The results reveal the importance of peers, those considered experts or "market mavens", and the need for information on the dangers of Pb as an outdated practice for any future intervention. This study advances the notion of a design shift within engineering WASH projects, whereby social/behavioral approaches are used to consider the needs, concerns, and current behaviors of the consumer. We also advocate for engaging intermediate players who often influence behavior change in the rollout of an engineering innovation.

In low- and middle-income countries (LMICs), the presence of an informal economy can lead to human exposure to toxic metals such as lead (Pb). This paper demonstrates the local health and economic benefits of modifying practices within the informal economic sector in Madagascar. Specifically, leaded components in 504 locally manufactured household water pumps were replaced with unleaded components. Prior to the intervention, 32% of the household systems exhibited lead concentrations above the World Health Organization (WHO) provisional drinking water guideline of 10 μg/L, but after the intervention, fewer than 3% of the systems were in exceedance. The reduction of lead concentration is modeled to reduce the fraction of children with elevated BLLs (>5 μg/dL) from 34 to 13%. The reduction in BLLs is estimated to provide an average economic benefit of US$11 800 per child based on predicted increases in lifetime productivity. This corresponds to a total benefit of US$8.7 million for the 730 children aged 1-5 associated with the pumps, representing a return on investment of greater than 1000-to-1. Results demonstrate how the formation of partnerships between public, private, and civil society entities, as suggested by UN Sustainable Development Goal 17, can realize important local economic and health benefits in LMICs.

A recent result obtained by means of an in vitro experiment with cancer cultured cells has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is made more significant by the fact that the reticular accumulation rate of FDG is dependent upon extracellular glucose availability. The objective of the present paper is to confirm in vivo the result obtained in vitro concerning the crucial role played by the endoplasmic reticulum in FDG cancer metabolism. This study utilizes data acquired by means of a Positron Emission Tomography scanner for small animals in the case of CT26 models of cancer tissues. The recorded concentration images are interpreted within the framework of a three-compartment model for FDG kinetics, which explicitly assumes that the endoplasmic reticulum is the dephosphorylation site for FDG in cancer cells. The numerical reduction of the compartmental model is performed by means of a regularized Gauss-Newton algorithm for numerical optimization. This analysis shows that the proposed three-compartment model equals the performance of a standard Sokoloff's two-compartment system in fitting the data. However, it provides estimates of some of the parameters, such as the phosphorylation rate of FDG, more consistent with prior biochemical information. These results are made more solid from a computational viewpoint by proving the identifiability and by performing a sensitivity analysis of the proposed compartment model., Competing Interests: The authors have declared that no competing interests exist.

This paper studies a system of Ordinary Differential Equations modeling a chemical reaction network and derives from it a simulation tool mimicking Loss of Function and Gain of Function mutations found in cancer cells. More specifically, from a theoretical perspective, our approach focuses on the determination of moiety conservation laws for the system and their relation with the corresponding stoichiometric surfaces. Then we show that Loss of Function mutations can be implemented in the model via modification of the initial conditions in the system, while Gain of Function mutations can be implemented by eliminating specific reactions. Finally, the model is utilized to examine in detail the G1-S phase of a colorectal cancer cell.

The coronavirus disease 2019 (COVID-19) pandemic has been closely tied with what has been called an infodemic, a "second disease" that occurs when massive information volumes (particularly with a high prevalence of false information) hinder the public health response. In this context, social listening, the process of monitoring and analyzing conversations to inform strategic activities both online and offline, becomes an even more essential component of risk communication and engagement strategies. In the Eastern and Southern Africa region, the United Nations Children's Fund (UNICEF) and partners in the response have activated their capacity to gather insights on the information needs of the populations served to better inform and engage with local communities. We describe the social listening approach taken at the Eastern and Southern Africa regional level to respond to COVID-19 and highlight efforts by the Comoros, Kenya, Madagascar, Malawi, and Zambia UNICEF country offices to implement digital and nondigital social listening to inform risk communication and community engagement. The analysis highlights channels leveraged, types of data monitored, and provides examples of social listening data use, as well as early challenges and lessons learned.

Background/objective: The understanding and practice of public health crisis communication are improved through the study of responses to past crises, but require retooling for present challenges. The 'Addressing Ebola and other outbreaks' checklist contains guiding principles built upon maxims developed from a World Health Organization consultation in response to the mad cow (bovine spongiform encephalopathy) crisis that were later adopted for Ebola. The purpose of this article is to adapt the checklist for the health communication challenges and public health practices that have emerged during the coronavirus disease 2019 (COVID-19) pandemic. The communication challenges of promoting vaccine acceptance are used to illustrate a key area that requires strengthened communication. Type of program or service: Effective communication principles for application during the COVID-19 pandemic., Results: The COVID-19 pandemic has introduced unique challenges for public health practitioners and health communicators that warrant an expansion of existing health communication principles to take into consideration: the new infodemic (or mis/disinfodemic) challenge - particularly as treatments and vaccines are being developed; communication of risk and uncertainty; health-information behaviours and the instantaneous nature of social media, and the relationship between media literacy and health literacy; the effects of the pandemic on other health issues; and the need for a flexible communication strategy that adapts to the different stages of the pandemic., Lessons Learnt: Principles discussed in this article will help build preparedness capacity and offer communication strategies for moving from the acute phase to the 'next normal' with likely prevention (e.g. herd immunity achieved through vaccination) and societal COVID-19 resilience., Competing Interests: None declared

In this work we use numerical simulation to investigate how the temporal length of the data affects the reliability of the estimates of brain connectivity from EEG time-series. We assume that the neural sources follow a stable MultiVariate AutoRegressive model, and consider three connectivity metrics: imaginary part of coherency (IC), generalized partial directed coherence (gPDC) and frequency-domain granger causality (fGC). In order to assess the statistical significance of the estimated values, we use the surrogate data test by generating phase-randomized and autoregressive surrogate data. We first consider the ideal case where we know the source time courses exactly. Here we show how, expectedly, even exact knowledge of the source time courses is not sufficient to provide reliable estimates of the connectivity when the number of samples gets small; however, while gPDC and fGC tend to provide a larger number of false positives, the IC becomes less sensitive to the presence of connectivity. Then we proceed with more realistic simulations, where the source time courses are estimated using eLORETA, and the EEG signal is affected by biological noise of increasing intensity. Using the ideal case as a reference, we show that the impact of biological noise on IC estimates is qualitatively different from the impact on gPDC and fGC.

Background: Magneto- and Electro-encephalography record the electromagnetic field generated by neural currents with high temporal frequency and good spatial resolution, and are therefore well suited for source localization in the time and in the frequency domain. In particular, localization of the generators of neural oscillations is very important in the study of cognitive processes in the healthy and in the pathological brain., New Method: We introduce the use of a Bayesian multi-dipole localization method in the frequency domain. Given the Fourier Transform of the data at one or multiple frequencies and/or trials, the algorithm approximates numerically the posterior distribution with Monte Carlo techniques., Results: We use synthetic data to show that the proposed method behaves well under a wide range of experimental conditions, including low signal-to-noise ratios and correlated sources. We use dipole clusters to mimic the effect of extended sources. In addition, we test the algorithm on real MEG data to confirm its feasibility., Comparison With Existing Method(s): Throughout the whole study, DICS (Dynamic Imaging of Coherent Sources) is used systematically as a benchmark. The two methods provide similar general pictures; the posterior distributions of the Bayesian approach contain much richer information at the price of a higher computational cost., Conclusions: The Bayesian method described in this paper represents a reliable approach for localization of multiple dipoles in the frequency domain., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background . Improving human papilloma virus (HPV) vaccination coverage in the US will require healthcare providers to recommend the vaccine more effectively. To inform quality improvement efforts, we systematically reviewed studies of dental provider communication about HPV vaccination. Methods . We searched MEDLINE, CINAHL, ScienceDirect, PsycINFO and JSTOR in August 2018 to identify studies of dental provider knowledge, perceived role and communication about HPV, HPV vaccination and HPV-associated oropharyngeal cancer (HPV-OPC). Results . We identified 10 qualitative and quantitative studies. Results of the primarily descriptive studies showed that although there were some deficiencies in knowledge about HPV-related outcomes and its effect on the male population, most providers understand HPV as a sexually transmitted infection and know the HPV vaccine is available, yet many are not discussing the HPV-OPC link or recommending vaccination. Providers were less often to recommend HPV vaccination if they were uncomfortable discussing sex, perceived parents as hesitant, or believed patients to be low risk. Studies reported mixed results on providers' perceived role in expanded HPV vaccination and HPV-OPC education, but indicated support for the role of professional organizations in promoting awareness. Conclusion . Interventions are needed to help dental providers perceive their role to deliver effective recommendations within the complex communication environment surrounding HPV vaccination and HPV-OPC education.

Background: Trans-arterial radio-embolization (TARE) is an emerging treatment for the management of hepatocellular carcinoma (HCC). TARE may compete with systemic chemotherapy, sorafenib, in intermediate stage patients with prior chemoembolization failure or advanced patients with tumoral macrovascular invasion with no extra-hepatic spread and good liver function. We performed a budget impact analysis (BIA) evaluating the expected changes in the expenditure for the Italian Healthcare Service within scenarios of increased utilization of TARE in place of sorafenib over the next five years., Methods: Starting from patient level data from three oncology centres in Italy, a Markov model was developed to project on a lifetime horizon survivals and costs associated to matched cohorts of intermediate-advanced HCC patients treated with TARE or sorafenib. The initial model has been integrated with epidemiological data to perform a BIA comparing the current scenario with 20 and 80% utilization rates for TARE and sorafenib, respectively, with increasing utilization rates of TARE of 30, 40 and 50% over the next 1, 3 and 5 years., Results: Compared to the current scenario, progressively increasing utilization rates of TARE over sorafenib in the next 5 years is expected to save globally about 7 million Euros., Conclusions: Radioembolization can be considered a valuable treatment option for patients with intermediate-advanced HCC. These findings enrich the evidence about the economic sustainability of TARE in comparison to standard systemic chemotherapy within the context of a national healthcare service.

Aim: We evaluated two treatment sequences, transarterial radioembolization followed by transarterial chemoembolization and possibly sorafenib (=TTS) versus transarterial radioembolization followed by sorafenib alone (=TS), to identify the most cost-effective pathway to treat intermediate-stage hepatocellular carcinoma from the Italian healthcare system perspective., Materials & Methods: A Markov model was developed to project costs and health outcomes for TTS and TS over a lifetime horizon. Data available at three hospitals in Italy were collected. Healthcare resource utilization was derived from standard clinical protocols. Costs were obtained from official regional tariffs., Results & Conclusion: Taking into consideration 16 patients for TTS and 22 patients for TS pathways, the TTS sequence provided a dominant strategy in comparison to TS. Further evidence is desirable to confirm these results.

Background: Evidence shows that territorial borders continue to have an impact on research collaboration in Europe. Knowledge of national research structural contexts is therefore crucial to the promotion of Europe-wide policies for research funding. Nevertheless, studies assessing and comparing research systems remain scarce. This paper aims to further the knowledge on national research landscapes in Europe, focusing on non-communicable disease (NCD) research in Italy and Germany., Methods: To capture the architecture of country-specific research funding systems, a three-fold strategy was adopted. First, a literature review was conducted to determine a list of key public, voluntary/private non-profit and commercial research funding organisations (RFOs). Second, an electronic survey was administered qualifying RFOs. Finally, survey results were integrated with semi-structured interviews with key opinion leaders in NCD research. Three major dimensions of interest were investigated - funding mechanisms, funding patterns and expectations regarding outputs., Results: The number of RFOs in Italy is four times larger than that in Germany and the Italian research system has more project funding instruments than the German system. Regarding the funding patterns towards NCD areas, in both countries, respiratory disease research resulted as the lowest funded, whereas cancer research was the target of most funding streams. The most reported expected outputs of funded research activity were scholarly publication of articles and reports., Conclusions: This cross-country comparison on the Italian and German research funding structures revealed substantial differences between the two systems. The current system is prone to duplicated research efforts, popular funding for some diseases and intransparency of research results. Future research will require addressing the need for better coordination of research funding efforts, even more so if European research efforts are to play a greater role.

Objectives: To perform a cost-effectiveness analysis comparing the use of transarterial radioembolization (TARE) with that of sorafenib in the treatment of patients with intermediate or advanced hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer staging system., Methods: Patient-level data were consecutively recorded and collected at three oncology centers in Italy. A propensity score matching was performed to compare patients with similar clinical characteristics who underwent TARE or sorafenib treatment. Clinical data from the matched cohorts were used to populate a Markov model to project, on a lifetime horizon, life years, quality-adjusted life years, and economic outcomes associated with TARE and sorafenib for both intermediate and advanced HCC stages., Results: Starting from data covering 389 and 241 patients who underwent TARE and sorafenib treatment, respectively, the propensity score matching yielded a total of 308 matched patients. For intermediate-stage patients, the model estimated for TARE versus sorafenib an incremental cost-utility ratio of €3,302/QALY (incremental cost-effectiveness ratio of €1,865 per life year gained), whereas for patients in advanced stage TARE dominated (lower costs and greater health improvements) compared with sorafenib., Conclusions: From an Italian health care service perspective, TARE could be a cost-effective strategy in comparison with sorafenib for patients with intermediate or advanced HCC. The results from forthcoming randomized controlled trials comparing TARE with sorafenib will be able to confirm or reject the validity of this preliminary evaluation. In the meantime, decision makers can use these results to control and coordinate the diffusion of the technology., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Trans-arterial radioembolization (TARE) is a recognized, although not explicitly recommended, experimental therapy for unresectable hepatocellular carcinoma (HCC).A systematic literature review was performed to identify published studies on the use of TARE in intermediate and advanced stages HCC exploring the efficacy and safety of this innovative treatment.Twenty-one studies reporting data on overall survival (OS) and time to progression (TTP), were included in a meta-analysis. The pooled post-TARE OS was 63% (95% CI: 56-70%) and 27% (95% CI: 21-33%) at 1- and 3-years respectively in intermediate stage HCC, whereas OS was 37% (95% CI: 26-50%) and 13% (95% CI: 9-18%) at the same time intervals in patients with sufficient liver function (Child-Pugh A-B7) but with an advanced HCC because of the presence of portal vein thrombosis. When an intermediate and advanced case-mix was considered, OS was 58% (95% CI: 48-67%) and 17% (95% CI: 12-23%) at 1- and 3-years respectively. As for TTP, only four studies reported data: the observed progression probability was 56% (95% CI: 41-70%) and 73% (95% CI: 56-87%) at 1 and 2 years respectively. The safety analysis, focused on the risk of liver decompensation after TARE, revealed a great variability, from 0-1% to more than 36% events, influenced by the number of procedures, patient Child-Pugh stage and treatment duration.Evidence supporting the use of radioembolization in HCC is mainly based on retrospective and prospective cohort studies. Based on this evidence, until the results of the ongoing randomized trials become available, radioembolization appears to be a viable treatment option for intermediate-advanced stage HCC.

Background: Chemotherapy-induced nausea and vomiting (CINV) is a particularly distressing event for oncology patients. This review aims at analyzing the impact of CINV on Health-Related Quality of Life (QoL) and on the use of healthcare resources., Methods: A systematic search was conducted according to the PRISMA statement on MEDLINE, EMBASE and NHS EED., Results: Sixty-seven studies were included in the final selection. Despite the availability of numerous treatment options, CINV was found to have a strong impact on HRQoL of patients. Direct costs are particularly affected, but this result could be due to scarcity of studies assessing indirect costs., Conclusions: Evidence supports the notion that CINV continues to have a negative impact on HRQoL of patients, even for those receiving moderately emetic chemotherapy. Further studies need also to collect data on the cost of CINV, particularly indirect costs, to ensure that decisions on use of healthcare resources are better supported., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Asthma and chronic obstructive pulmonary disease (COPD) are disorders of the lungs characterized by airflow obstruction, inflammation and tissue remodeling. Management of patients with these diseases is complex and the improvement of diagnostic-therapeutic strategies represents a critical challenge for the healthcare system. In this context, investigating the criteria and information needed for an appropriate and effective evaluation of incoming treatment options is crucial to ensure that clinicians and policy-makers are provided with the best available evidence to make decisions aimed at improving patient outcomes. Therefore, the objective of this study was to investigate the degree of agreement among Health Technology Assessment (HTA) experts on issues crucial to the evaluation of new drugs for asthma and COPD and to appropriately manage the clinical pathway for patients., Method: This research was conducted using an e-Delphi technique organized in three subsequent rounds and involving a panel of ten experts (six regional and local payers and four clinicians). Panelists were asked to comment in written form on a set of statements, explaining qualitatively the extent to which they agreed or disagreed with the assertions. Statements were subsequently modified and resubmitted for assessment., Results: Panelists expressed their opinions during each round and, after round III, a consensus document was finalized. The degree of consensus was high among experts and concerned five main topics: (a) the need to address current unmet needs of patients with asthma or COPD, (b) the importance of further studies and real-life information in the evaluation of treatments, (c) existing evidence and evidence needed to assess drugs, (d) critical issues in obtaining a positive evaluation from regional and local authorities for new treatments to be included in regional formularies and to have an important place in therapeutic categories, and (e) the major obstacles to the appropriate administration of drugs and management of patients., Conclusion: The final document highlights that no proof of difference among drugs exists, that evidence on final endpoints (and particularly on mortality) should be strengthened and that actions regarding risk factors, appropriate diagnosis, patient staging and adherence to therapy are particularly important for a better clinical management.

Context: The process of care for patients with prostate cancer is subject to different degrees of uncertainty. Patients and clinicians could, therefore, greatly benefit from improved prognostic instruments. One emerging tool is the cell cycle progression (CCP) score., Objective: This systematic review assesses evidence on the value of the CCP instrument in prostate cancer treatment by reviewing current publications and integrating the results via a meta-analysis., Evidence Acquisition: We performed a review of Medline and Embase in April 2014, according to Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). Unpublished studies were retrieved from the 2013-2014 proceedings of major conferences in the field. Sixteen publications were selected for inclusion., Evidence Synthesis: The results show that use of the CCP score is better than existing assessments at elucidating the aggressive potential of prostate cancer in an individual. The pooled hazard ratio for biochemical recurrence per 1-unit increase in the CCP score was 1.88 in a univariate model and 1.63 in a multivariate model. Four studies showed that CCP testing can impact the decisions of physicians regarding treatment, and potentially lead to a decrease in surgical interventions for low-risk patients., Conclusions: This review offers a comprehensive overview of existing evidence on CCP testing, and provides clinicians, patients, and policy makers with a strong summary measure of its prognostic validity and clinical utility. It will be important to develop economic studies to measure the impact of such technology on health care systems., Patient Summary: In this paper, we review current evidence related to the cell cycle progression (CCP) score for patients with prostate cancer. We found good evidence suggesting that use of the CCP score improves prognosis, and can be a valuable tool for clinicians in treating patients. The economic benefits are yet to be studied., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The authors comment the data from research on 70 patients with post cholecystectomy syndrome, using cholescintigraphy HIDA 99mTc to evaluate the relation ship between symptomatology (see classific.) and duodenogastric reflux entity. Cholescintigraphy seems to be a valid clinical means, especially for a correct indication to endoscopy.

Brucellosis may show itself only through its bone and muscle complications, especially in the lumbar region, such as vertebral colliquation or psoas abscess. The authors describe a case of brucellosis (56 year old male, butcher) with lumbar bone and muscle involvement. The first symptom was a persistent pain of the right lumbar region, with irradiation to the homolateral leg. At admission the patient showed a lumbar cutaneous fistula with pus-like secretion. Quick diagnosis and therapy can prevent irreparable damage, even when the symptoms are silent.

The paper outlines the indications for the use of Kehr's tube in the surgical management of extra-hepatic biliary lithiasis by reporting the authors' personal experience relating to the period 1988-1992. In line with data reported in the literature the paper emphasizes the value of Kehr's tube not only in those cases where it is necessary to prevent choledochotomy and radiological control, but above all were the postoperative possibility of removing any residual calculi using litholytic, endoscopic or lithotripsic methods, is of prime importance.

The authors describe two years and six months of personal experience in the treatment of recurrent inguinal hernia with polypropylene mesh. There was a follow-up with controls every 6 months with excellent results. From the data of the operation we programmed a further control 1'after 5 and 10 years. Considering the limited number of cases and the fact that the follow-up is not yet at completion, the information is provided as preliminary.

The paper analyses the authors' initial experience of video laparoscopic cholecystectomy, outing the difficulties and incidence of morbidity in the preliminary group of 38 patients. The details of complications and their pathogenesis are also reported.

Following a brief review of the main method of prosthetic repair used for inguinal hernia: Lichtenstein, Stoppa, Rives, etc, the authors propose an original technique consisting in the placement of a marlex patch below the trasversalis fascia, in a pre-peritoneal site, using a classical inguinal access route. The prosthesis is fitted round the spermatic funicle and fixed with a single stitch to the pubis and with a few others, in resorbable material, to the posterior face of the trasversalis fascia. Above it, plastic surgery is performed to bring the triple stratum closer to the reflexio of the inguinal ligament. The prosthesis is kept in place by positive abdominal pressure. The method outlined here has been used in 71 cases of primary or recurrent inguinal hernia. Follow-up lasted for 1-24 months and showed the low morbidity (4.5%) due to sepsis of the surgical wound, which did not require reoperation, and only 1 case of recurrent hernia which was probably caused by the incorrect positioning of the prosthesis.