Responsible: Eng. Mauro Grigioni
phone: (+39) 06 4990 6535
The National Center for Innovative Technologies in Public Health (TISP) promotes the improvement of the state of public health through research, development, optimization and evaluation of innovative technologies for the protection of public health using multidisciplinary skills. The field of activity ranges from medical devices, to biomedical engineering, radiological health, nuclear medicine, nanotechnology and innovative therapies.
The Center, using multidisciplinary skills, carries out research and training activities in the fields of radiobiology, quality assurance in the radiological sciences, nuclear medicine, bioengineering, medical devices, regenerative medicine, electron microscopy, nanotechnology and innovative therapies.
Organization of the center
The Center has autonomous prototyping (electronics, mechanics, hydraulics) and thematic laboratories for research and innovation. There are the following areas:
1. Strategic area of Radiological Sciences; Referrals: Maria Antonella Tabocchini, Antonella Rosi
2. Strategic area of nuclear medicine; Referrals: Evaristo Cisbani, Maria Antonella Tabocchini
3. Strategic area of biomedical engineering; Referrals: Mauro Grigioni, Rossella Bedini
4. Strategic area of medical devices; Referrals: Carla Daniele, Alberto Renzoni
5. Strategic area of Nanotechnology; Referrals: Fabiana Superti, Mauro Grigioni
6. Strategic area of innovative therapies; Referrals: Fabiana Superti, Rossella Bedini
The six strategic areas collaborate with other structures of the Italian National Institute of Health (ISS) providing experts for the institutional activities of drafting opinions, e.g. for law 26/2014 and the community directives, in their respective areas of competence.
The center participates in the NanoTecnologie temporary mission structure.
Electron microscopy. Referrals: Fabiana Superti
Mechanical workshop. Referrals: Giorgio De Angelis, Fabio Santavenere
Elettronica. Contact persons: Gianni Maccioni, Angelo Angeloni, Fausto Giuliani
IT management of the Center. Referrals: Alessandro Spurio, Carmelo Notaro
TISP editorial board. Contact person: Paola Meli
Facilities of radiation. Referrals: Giuseppe Esposito, Maria Antonella Tabocchini
Cybersecurity working group
Contact person : Mauro Grigioni
1) Radiological sciences
The groups involved are concerned with optimizing the use of ionizing radiation in radiotherapy and radiodiagnostics; evaluation of radiation damage and quality assurance requirements.
Research is aimed at the study of the biological efficacy of radiation to the tumor target and of the undesirable effects on healthy tissue and the evaluation of the radiation risk in a regime of low doses and variable dose rates, of particular relevance in radiodiagnostics and in nuclear medicine.
The studies on the mechanisms underlying the radio-induced effects are carried out in cells or organisms in the different exposure scenarios both to photons, commonly used in the clinic, and to charged particles, currently of extreme interest in complex procedures such as hadrontherapy.
The systematic study based on the increase in the dose rate starting from values below the natural background is aimed at obtaining useful data for the validation of the linear model without threshold used for the extrapolation of the risk of radiation carcinogenesis.
Another approach in the study of chemo response and radiotherapy treatments and towards a personalized therapy, is the identification of metabolic biomarkers through Nuclear Magnetic Resonance metabolomics of biological samples such as cellular / tissue model systems and biological fluids of different origins. The identification and characterization of metabolic profiles is essential for the detailed description of the interactions between metabolites and for the understanding of metabolic paths and their alteration as a response to external and internal stimuli.
In the field of Oncological Hadrontherapy, the ENEA-IFO-ISS collaboration, with the financial support of the Lazio Region, is engaged in the TOP-IMPLART project (Oncological Therapy with Protons - Intensity Modulated Proton Linear Accelerator for RadioTherapy) for the construction of the first accelerator linear for hadrotherapy. The activity concerns the radiobiological and dosimetric characterization of the proton beam; the preparation of a vertical line dedicated to radiobiology studies; the design, construction and operation of the dose release system and diagnostics components of related beams and the development of an innovative system for measuring the energy of the beam.
The highly interdisciplinary research activities are carried out in collaboration with other groups of the Italian National Institute of Health and with other institutions (in particular INFN, ENEA and IRCCS).
The institutional activities are closely related to the research activities and are aimed at the implementation of Quality Assurance Programs through the coordination of multidisciplinary Study Groups in Radiotherapy (including proton therapy which is conquering an important space in the field of public health), Radiodiagnostics, Interventional Radiology for the continuous improvement of quality in radiological sciences. This activity involves the participation of all scientific associations / federations in the sector.
At the European level, ISS contacts have been used for:
- MELODI Platform - EURATOM.
MELODI (Multidisciplinary European Low Dose Initiative) is a transnational organization whose mission is to coordinate and promote European research on the risks associated with exposure to low doses of ionizing radiation. The ISS was one of the founding members of the Platform which, to date, is made up of 44 members from different European countries. Among the main activities is the definition and continuous updating of a long-term (> 20 years) Strategic Research Agenda (SRA) for research in the sector, maintaining a high level of expertise in radiological sciences and radiation protection and promoting access and sustainability of infrastructures of interest. MELODI has established close relationships through Memorandum of Understanding (MoU) with other European Platforms involved in radioprotection research (i.e., ALLIANCE for radioecology, NERIS for emergencies, EURADOS for dosimetry, EURAMED for medical aspects).
Together the 5 platforms identify priorities for guiding national and European research programs and for the preparation of competitive EURATOM calls, contribute to the dissemination of knowledge and constitute an interface with international partners such as World Health Organization (WHO), United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), International Conference on Recovery after Nuclear Accidents (ICRP) and International Atomic Energy Agency (IAEA).
- EJP CONCERT (UO) - EURATOM
The European Joint Program for the integration of radiation protection research (CONCERT) operates within the European Community Horizon 2020 funding program for research and innovation for joint research initiatives proposed by the European research platforms on the protection from radiation (MELODI, ALLIANCE, NERIS, EURADOS and EURAMED). To stimulate an active dialogue with all subjects who have a significant interest in radiation protection in the context of Task 5.3, a questionnaire has been developed that addresses an audience of non-specialists, to assess their perception of the radiological and nuclear risk and their opinion on related issues such as communication and information received from different actors. The questionnaire in 15 languages was launched at European level through institutional channels and social media (2000 responses of which 600 in Italy). The analysis of the results is currently underway which will be used to address future research in radiation protection
- MEDIRAD (UO) - EURATOM project
MEDIRAD's objective is to improve radiation protection practices through three main operational purposes: i) to improve the estimate of the dose to the organs and how it is recorded; ii) evaluate and understand the mechanisms underlying the effects due to medical exposure, focusing in particular on two results relevant to public health: the cardiovascular effects induced by radiation therapy in the treatment of breast cancer and the risk of carcinogenesis following CT scans in pediatrics iii) develop recommendations based on scientific evidence and a consensus policy aimed at optimizing patient radiation protection.
2) Nuclear Medicine
Use of nuclear radiation for innovative and increasingly effective applications for public health and evaluation of their overall benefit; improvement of quality standards in nuclear medicine.
The activity of the group of nuclear physicists and biologists is engaged in the development of innovative instrumentation for imaging with radiopharmaceuticals, widely used especially in the identification, accurate staging and / or therapy of tumors, but also in the diagnosis of cardiovascular and neurological diseases.
In recent years, activities have focused on the development of new devices for:
- early detection of breast and prostate cancers
- preclinical studies of new radiopharmaceuticals and innovative therapies
- support for greater customization of radiometabolic therapies, considered among the most promising applications of ionizing radiation in the oncological field
These activities are carried out in collaboration with researchers from other national and international bodies and universities.
The Center is the promoter and coordinator of a working group for Quality Assurance in Nuclear Medicine which involves experts from the main professional associations in the sector.
3) Biomedical engineering
The diagnostic and therapeutic offer is currently subject to increasing pressure, due to the increase in the average age of the subjects and the need to allocate limited resources in the face of an increase in technological possibilities. In this context, biomedical engineering can offer valuable help to the National Health Service (SSN), making use of patient modeling methodologies or more generally of biological systems, applying principles of electrical, chemical, mechanical, optical engineering, etc.
For example, biomedical engineering is able to make a significant contribution to personalized medicine (with evident outcome improvements compared to traditional approaches), through the construction of virtual patient models and study of possible surgical options.
The studies of the TISP center can be traced back to a biomechanical field, in particular to the fluid dynamics of the cardiovascular system, biomechanics of human movement, with consolidated experience in rehabilitation engineering, through the design and construction of prototypes for the measurement of relevant biomechanical parameters.
The staff of the TISP center is active in various sectors of biomechanics, ranging from the functional and structural characterization of medical devices to mechatronics / robotics in the motor case, and in particular to wireless sensitization, creating kits for applications in the home and clinic. State-of-the-art in vitro instruments are available for fluid dynamic measurements on DM (PIV, LDA, Hot-film Anemometry), as well as resources for the numerical simulation of fluid dynamics of biological flows, also participating in the in-vivo experimentation phases on animals, for special searches.
It is therefore possible to compare experimental and numerical results on the same study objects. It is also possible to design prototypes for research, complete systems for metrological detection, to create electronic instrumentation, and programming and control of devices for recording and conditioning physiological signals from wireless devices for motion analysis. These activities find an outlet in telemedicine (telemonitoring, telereferencing, telecitology, telesurgery, etc.) with relevance in the studies of movement for the purpose of assistance and rehabilitation in the telematic version. Examples in particular are tele-rehabilitation and tele-assistance, with the implications in the definition of new health intervention models for continuity of care, as in the case of complex pathologies such as Parkinson, Alzheimer and COPD, with rehabilitation interventions such as motor, cognitive and cardio-respiratory, subject of research projects, with important repercussions in eHealth, mobile Health and telemedicine, from an organizational point of view. The research topics of the TISP center are the applications of Big Data, Artificial Intelligence, Analytics, Cyber Security for medical devices in favor of the governance of the technologies of the National Health System, such as for example the management and renewal of the diagnostic-therapeutic technology park.
The TISP center also has extensive experience of collaboration with the cardiac surgery department of the Bambino Gesù pediatric hospital in Rome, aimed at assessing the outcome in surgical treatment of the univentricular patient, who must face a very serious congenital pathology (presence of only one functional ventricle), experimentally studying the fluid dynamic optimization of the standard surgical connection (PIV, LDA, CFD) even in the presence of secondary anomalies (stenosis of the pulmonary arteries).
- High-end and Low-End Virtual Reality Systems for the Evaluation, Training and Rehabilitation of Frailty in the Elderly (UO) funded by Italian MoH, Notice of the Ministry of Health Finalized 2013
- Development and validation of a robotic platform for motor rehabilitation and visuomotor coordination of the upper limbs with virtual reality scenarios related to daily life activities (UO), funded by INAIL, BRIC 2016
- Cardiac regeneration: Characterization, optimization and evaluation of force developed by engineered tissue obtained from spontaneous or scaffold-based 3D culture of pediatric human adipose tissue-derived mesenchymal stem cells (UO), funded by Italian MoH, Notice of the Ministry of Health Finalized 2013
4) Medical devices
The TISP center has considerable experience in the medical device (MD) sector, traditionally studied both from an experimental point of view (developing test protocols for many types of high-risk class medical devices, in particular for cardiovascular implants such as valves, stents, vascular prostheses, cardiac support devices) and from the regulatory one.
This strategic area contributes to the technical-regulatory cultural support necessary to face the risk assessment of health technologies, also by setting up experimental test laboratories for the characterization of Medical Devices (institutional activity) and state-of-the-art measurement systems for scientific research. The technology assessment activities are based on the EU directives for the MD (93/42 / EEC and 90/385 / EEC), the risk analysis of innovative technologies (EN ISO 14971), the Horizon Scanning and the Health Technology Assessment.
Technical and scientific support is provided to the Ministry of Health in relation to clinical control and experimentation on medical devices. Consultancy and support also concern other SSN subjects, within the framework of agreements aimed at improving the healthcare offer in specific areas of intervention (BCPO, SLA, Aids)
Still within the institutional work of the ISS, the TISP center provides, among others, opinions on:
- animal testing projects using biomaterials and medical devices
- presence and characterization of foreign bodies in drugs and food
- mechanical safety tests on toys and consumer products according to European legislation in support of other departments / centers
A mechanical workshop and electronics services are available for the construction of prototypes necessary for the execution of the measures requested by the Ministry of Health, the NAS, or by private individuals in collaboration.
Finally, the TISP center is active in the study and development of new devices for tissue engineering and nanotechnology, both in research and from a regulatory point of view.
Among the innovative medical devices studied by the TISP center in recent times, the MDs realized with 3D printing techniques and the nanostructured MDs, the latter, in particular, exploit the peculiar characteristics of the materials at the nanoscale, for which even surprising quantum effects are highlighted, in the sense that the traditional characteristics of bulk materials are often contradicted by the properties of nanostructured materials having the same chemical composition (an example is nanostructured gold, which can act as a strong catalyst of enzymatic reactions, as opposed to what is known for traditionally worked gold). The peculiar properties of nanomaterials pose both great opportunities for manufacturing innovative MDs and potential problems, as nanoscale materials interact strongly with cells and subcellular structures (e.g., cells tend to internalize many types of nanoparticles, with possible cytotoxic effects), therefore it is necessary to ascertain safety in the use of nanostructured MDs.
The TISP Center also deals with the safety of body decoration practices, such as: tattoo, permanent makeup and piercing. These practices, increasingly popular in the population, are invasive procedures. For this reason, in addition to highlighting the critical issues, it is important to improve the safety conditions in which these procedures are carried out and to make the population aware of the risks they face. A sector of particular interest is made up of tattoos for medical purposes, which are used to restore the appearance of healthy skin and / or as a complement to reconstructive surgery. One of the objectives of the Center is to deepen and disseminate knowledge of the benefits that citizens can take advantage of through the use of this type of tattoo. In this regard, we are carrying out further studies, in collaboration with health facilities in which there are Breast Units that perform surgical removal of breast cancer and subsequent reconstruction, aimed at developing a standardized operating protocol for the tattoo of the areola-nipple complex.
The TISP Center also studies the devices that fall within the field of Assistive Technologies (AT), intended for the severely disabled and more generally disabled people aimed at people with frailty.
Consensus Conference on Robotics in Rehabilitation: the first meeting of the Technical-Scientific Committee of the consensus conference on robot-assisted rehabilitation and electromechanical devices for people with disabling diseases of neurological origin starts
The Italian National Institute of Health hosts the first meeting of the Technical Scientific Committee of the National Consensus Conference, promoted by the Italian Society of Physical and Rehabilitation Medicine (SIMFER) and by the Italian Society of Rehabilitation (SIRN), dedicated to robot-assisted rehabilitation for people with disabling pathologies of neurological origin and whose final celebration is scheduled for the first half of 2020.
The growing use of robotic systems and electromechanical devices in the field of neurological rehabilitation has highlighted the need to create a shared framework of reference and to standardize criteria and methodologies in the clinical use of these technologies, both in relation to the organizational contexts in which they are provided, and in the evaluation of treatment outcomes.
The tasks of the Technical-Scientific Committee in this first phase will be:
- final definition of the stakeholder panel
- preparation of questions to be submitted to the jury
- definition of the working groups for the preparation of the preparatory documents
The multidisciplinary working group that makes up the Technical-Scientific Committee sees the ISS represented by Mauro Grigioni, Director of the National Center for Innovative Technologies in Public Health and will boast the participation of the representatives of the Medical Scientific Society of the sector, bioengineering, health economics, bioethics, the Health Technology Assessment, members of associations of health professionals of Rehabilitation and associations of people with disabilities.
Surgical planning and experimental tests (Personalized Medicine)
The Cardiovascular Biomechanical Unit of the National Center for Public Health has for many years supported pediatric cardiac surgery through hemodynamics studies in models of congenital cardiovascular diseases made of blown glass thanks to the technical skills present in ISS; it was thus possible to study the expected response of the reduction and reperfusion surgery of the organs by correcting stagnation and high cutting stress (shear stress).
Today the same group can implement surgical planning starting from nuclear magnetic resonance imaging (MRI) by reconstructing in-silico numerical models of the pathological districts, simulating the hemodynamic response using refined 3D velocimetry techniques starting from 3D printed anatomical representation.
- characterize nanomaterials (NM) present in everyday products or in medical devices (MD)
- study the interaction between cells (respiratory, intestinal and other) and NM, in relation to their physical-chemical characteristics, in the context of the risk / benefit identification linked to nanotechnology
- analyze the effects of exposure to NM, present in products of daily use or in MD, with particular regard to the analysis of potential risks of increased susceptibility to infections, in order to improve understanding of their potential impact on human health
The group's research, focused on some main objectives such as the study of the pathogenesis of viral and bacterial infections and the study of the impact of nanotechnology on health, is structured as follows:
- study by scanning (SEM) and transmission (TEM) electron microscopy of cellular and subcellular damage induced by infectious agents and the effect of exposure to NM on the susceptibility to infections of viral and bacterial origin, with particular regard to new or pathogenic emerging agents
- development and implementation of SOP, development of methods for the chemical-physical characterization of NM, of nanostructured medical devices (MD-NM) and of NM suspensions to be used in in vitro toxicity tests using analytical electron microscopy (SEM / EDX) and transmission electron microscopy (TEM)
- use of nanotechnologies aimed at optimizing the biocompatibility of the materials making up medical devices
Research is conducted through multidisciplinary approaches (ultrastructural, physical, biological, microbiological, biochemical and molecular) also in collaboration with other groups of the Italian National Institute of Health and with other institutions.
This area follows the regulatory aspects and the development of nanomaterials and nanostructured medical devices. As reaffirmed by the most recent industry standards, it is necessary to develop alternative methodologies for carrying out Biocompatibility tests (in particular cytotoxicity) of the nanomaterials used for the design and development of the MD, comparing the result with the traditional methods reported in the standards (in particular the EN ISO 10993 series) and critically discussing its effectiveness and limitations, considering the interactions with the nanomaterial and the elective method of analysis and risk management for MD (EN ISO 14971 standard).
The TISP center is particularly active in the development of cytotoxicity assessment methodologies of nanomaterials of interest in the production of MD: for this purpose, the impedance metric method has been developed which allows real-time monitoring of cell monolayers subjected to different concentrations of potentially toxic agents (nanoparticles); the results are compared with more traditional methods (MTT, Neutral red, cloning efficiency, etc.), as found in the presentations of the seminars and conferences of the RinnovaReNano project, funded by the Lazio Region. The TISP center also contributed to this project in terms of recognition of regulatory developments and technology transfer (seminar activities, creation of content for the thematic website).
MDs made with nanostructures are subject to experimental biomechanical tests, traditionally necessary as regards the physical characteristics of the final product (e.g., resistance to stress), at the laboratories available in the TISP center.
An important area of application of nanotechnology for the production of medical devices is Regenerative Medicine, which aims to create tissue or organ substitutes, through complex engineering and biological production processes.
Given the interdisciplinary nature of this sector, the related activities of the TISP center are characterized by a high level of collaboration between research groups both inside and outside the center, mainly with university groups. The staff of the center organizes an annual conference within the FORM (Forum on Regenerative Medicine).
The Nanotechnology Strategic Area was responsible for 4 Operating Units in the RinnovaReNano project, contributing to the implementation of characterization methods and the transferability of in vitro methods for the biological safety assessment of nanostructured medical devices (DM-NP) or carriers of nanostructures. The results of these activities were the subject of presentations at workshops and conferences.
The Ultrastructural Area is also responsible for an INAIL BRIC project aimed at studying the potential infectious risks in workers exposed to nanomaterials.
- RinnovaReNano project, financed by the Lazio Region (4 TISP Operating Units)
- BRIC project: Interaction between gold nanoparticles and respiratory cells: ultrastructural and virological investigations on internalization processes and on the modulation of susceptibility to viral respiratory infections in relation to the physical / chemical characteristics of the nanoparticles, funded by INAIL (PI)
6) Innovative therapies
In this strategic area, research is conducted on innovative approaches for therapies in different areas: antimicrobial, oncological and obesity.
One of the topics of study for antimicrobial therapies concerns the development of new strategies for the fight against infections, particularly regard to the development of innovative approaches and combinations of conventional antimicrobial therapies with substances of natural or synthetic origin (small molecules) to counter drug resistance and enhance the effectiveness of treatments in order to obtain a better quality of life for the patient. Research is conducted through multidisciplinary approaches (microbiological, biochemical, molecular and ultrastructural) also in collaboration with other groups of the Italian National Institute of Health and with other institutions. Particular attention is paid to the study of antimicrobial peptides derived from proteins of the innate immune system. These peptides have a broad spectrum of action against viruses, bacteria, fungi and protozoa, show synergistic activity with conventional drugs and other antimicrobial peptides and efficacy towards drug-resistant pathogens. The antimicrobial peptides are studied "as they are" or modified through various methodological approaches (e.g. Ala-Scan, synthesis of peptidomimetics) with the aim of identifying the sequence, conformation and amino acid residues crucial for biological activity.
The main purpose of this research is to identify the peptides that have the best therapeutic index for protection from infections.
In cancer therapies it is important to evaluate the effects of new procedures in preliminary in vitro studies on small animals. A very important contribution, in order to proceed in the development of a new therapy, is to evaluate the bone alterations that can result in the application. Through morphometric analyzes carried out with 3D microtomography instrumentation it is possible to evaluate and quantify all the characteristics and alterations of the trabecular and cortical bone, usually of femurs and / or tibia of small animals, in order to continue the study of therapy or decide variations of the same.
In the study and therapies against obesity it is important to have a knowledge and a preliminary study of the effects both of drugs and of variation of the dosages of the elements of the degenerative, cellular and metabolic process, mainly in vivo on a small animal. One of the effects that is studied is the damage to bone structures, examining the alterations that can occur, through in-vitro three-dimensional morphometry, of both the trabecular and cortical bone of femurs of small animals.
APP, software for medical uses, digital therapies, new regulations and possible risks and governance actions of the medical device market. These are complex problems on which industry, doctors and patients ask public decision-makers for clarity and standards. Today the Kick-off meeting of the working group of the SaMD Observatory, Software as Medical Device, was held. The working group, created on mandate from the Ministry of Health, is led by the Innovative Technologies in Public Health (TISP) center of the Italian National Institutes of Health, with internal experts from the TISP, TETA and CORI centers and external experts from the Medical Devices Confederation, ISO and Uninfo regulatory bodies, the European Public Health Alliance (EPHA), the CNR, the Mario Negri institute, the AIFM, and the universities of Bologna and Udine.
The main objective of the Observatory is the definition of methodologies for the classification and evaluation of stand-alone software such as medical devices (SaMD) and non-MD software (SnMD), but still of interest to health, to facilitate surveillance and a regulated adoption.
In detail, the SaMD Observatory will carry out:
a) monitoring the national and international situation regarding the classification and evaluation criteria of SaMD and SnMD, which can be used in the health sector, then defining classification and evaluation protocols for the software in question
b) design and subsequently the realization of classification and automatic evaluation protocols of products such as APP and other types of stand-alone software, freely available to the consumer (for example software commonly defined as Artificial Intelligence, AI).
c) necessary evaluation in relation to the key issues of Cyber Security and to the issues related to Big Data (MD connected to the network)
d) detection of secondary effects with respect to the intended use of the SaMD
e) dissemination of the results obtained
The initial meeting of the project partners highlighted how digital healthcare is now articulated in many aspects, many of which (e.g. APP, IA) characterized by the entry of many new players, who in some cases come from non-European countries thanks to the Network. The current situation has an undoubtedly positive side, as market access is much easier for these innovative products than for traditional biomedical technologies (more focused on the hardware part, therefore associated with high development costs). On the other hand, this ease of access to the market greatly complicates the governance processes of the system as a whole.
The observatory will provide a set of useful tools for programming and governing digital healthcare, framing new opportunities in the correct regulatory reference. It will also be a reference for correct information and evaluation of SaMD and SnMD for industry, doctors and citizens, the latter often unable to identify the most appropriate IT tools for his needs, among all those freely available.
Conferences organized by TISP in recent years:
• The figure of the caregiver: technologies and aids to improve the quality of life
• Innovative technologies for frail and disabled people
• Devices and aids in Augmentative and Alternative Communication and Assistive Technologies
• The role of Innovative Technologies in Public Health
• MEDAMI 2017 - V MEDiterranean thematic workshop in Advanced Molecular Imaging
• Probing transverse nucleon structure at high momentum transfer
• MEDAMI 2014 - III MEDiterranean thematic workshop in Advanced Molecular Imaging
Women's health: in vitro study of the action of probiotics and prebiotics on aerobic vaginitis (PI) funded by GIELLEPI S.p.A.
• Italian patent No. 0001408732: Lactoferrin peptides for use as broad spectrum inhibitors of influenza virus infection
• European Patent publication number EP 2780365: Lactoferrin derived peptides for use as broad-spectrum inhibitors of influenza virus infection