The COVID-19 pandemic has lasted from 2019 to 2022, severely disrupting human health and daily life. The combined effects of spatial, environmental, and behavioral factors on indoor COVID-19 spread and their interactions are usually ignored. Especially, there is a lack of discussion on the role of spatial factors in reducing the risk of virus transmission in complex and diverse indoor environments. This paper endeavours to summarize the spatial factors and their effects involved in indoor virus transmission. The process of release, transport, and intake of SARS-CoV-2 was reviewed, and six transmission routes according to spatial distance and exposure way were classified. The triangular relationship between spatial, environmental and occupant behavioral parameters during virus transmission was discussed. The detailed effects of spatial parameters on droplet-based, surface-based and air-based transmission processes and virus viability were summarized. We found that spatial layout, public-facility design and openings have a significant indirect impact on the indoor virus distribution and transmission by affecting occupant behavior, indoor airflow field and virus stability. We proposed a space-based indoor multi-route infection risk assessment framework, in which the 3D building model containing detailed spatial information, occupant behavior model, virus-spread model and infection-risk calculation model are linked together. It is also applicable to other, similar, respiratory infectious diseases such as SARS, influenza, etc. This study contributes to developing building-level, infection-risk assessment models, which could help building practitioners make better decisions to improve the building’s epidemic-resistance performance. As of 29 April 2022, the total number of COVID-19 cases globally exceeded 566,977,818, with more than 6,376,503 reported deaths .While aerosol transmission of COVID-19 is not listed as the main route of transmission, 239 scientists have published an open letter to the WHO supporting and proving that aerosol transmission was the most likely mechanism explaining the spatial pattern of COVID-19 infections . Virus tArchitectural design has a significant impact on indoor natural ventilation, occupants’ movement, behavior, interactions with the environment interface and each other, and the spread of microorganisms . Shao etSome risk assessment models have been proposed to help reduce the risk of indoor transmission. Peng et al.  presenteThis study aims to provide insights into the spatial factors involved and their roles in the indoor spread of the virus and to propose a spatial-based, multi-pathway infection-risk assessment framework. To analyse different aspects of this topic, we conducted a broad search on the databases “Web of Science” and “Google Scholar”. The search string is a combination of different keywords:  and (“COVID-19” or “COVID” or “SARS-CoV-2” or “coronavirus” or “epidemic” or “pandemic” or “respiratory disease” or “infectious diseases”) and (“relationship” or “association” or “effect” or “impact” or “influence” or “connection” or “correlation” or “link” or “linkage”). Initially, the broad search returned 549 papers, 139 of which were duplications or not in English. Through the screening of the titles and abstracts, 361 weakly relevant papers were found and eliminated. The main inclusion criteria in this stage were those papers that have at least one spatial design factors affecting the spread of pathogen. The full texts of 49 papers were reviewed and 32 papers were added manually from the reference checks. Finally, 55 papers were relevant to our main review questions and were included in our analysis .SARS-CoV-2 is the virus that causes COVID-19, and its genetic material is packaged in an outer layer (envelope) of proteins and lipids. The virions are spherical in outline, with diameters ranging from 60 to 140 nm . SARS-CoThe respiratory droplets (RDs) and expiratory flow features involved in expiratory activities determine the fate of droplets, including evaporation, deposition, aerosolization and exposure patterns. Previous studies have investigated the production and characteristics of exhaled droplets by experiment, including solid impaction, high-speed photography, optical technology, charge separation, etc. . Table 1After being expelled, RDs are exposed to relatively dry air as they move through the ambient environment, and their initial size determines their evaporation, deposition, and dispersion. Large droplets >100 μm will fall to any surface encountered  under the force of gravity following a ballistic trajectory . Most particles ≤50 μm evaporate into dry particles or aerosols during falling, which is suspended in the air long enough to be inhaled by susceptible people over short or long distances . The droThere are also many factors that affect droplet evaporation and deposition rates, such as initial droplet velocity, temperature, humidity, turbulence, etc. Elevated ambient temperature can accelerate the process of droplet evaporation. The median evaporation time for droplets with a diameter of 12 μm decreased by 71% (from 1.44 s to 0.42 s) as the ambient temperature increased from 5 °C to 35 °C . Dry airThere are generally four ways of virus exposure as follows: (1) respiratory fluid exchange between facial membrane, (2) RDs deposition by direct splash on exposed facial membrane, (3) touching facial membrane with hands contaminated with RDs or virus-bearing surfaces, and (4) inhalation of fine RDs and droplet nuclei. The virus can cause infections in different organs of the body, but the relationship between the location of virus deposition and the mechanism of infection remains unclear. In the first three exposures, the viral particles can trigger an infection once they meet the facial membrane. For the fourth, inhaled particles can deposit on the surface of the respiratory tract and cause infection. The nose is reportedly more sensitive to SARS-CoV-2 than the mouth and eyes . Larger 2, only about 1.2% of the frontal area of the head [COVID-19 is thought to spread mainly through close contact, which is defined as any full or partial face-to-face interaction with an infected person within 1.5 m . During the head , where othe head . The sigthe head . Updatedthe head . Multiplthe head . The outthe head  and the the head , was prethe head . Faecal-the head . TherefoImmediate physical contact, including face, hands, and other exposed skin;Personal fomite contact, including clothes, glasses, hats, ties, telephones, and other items passed by hand;Face-to-face contact, including being coughed or sneezed on or talking within 1 m.Having been within 1.5 m without face-to-face contact,and; 2 types of long-range exposure:Contact contaminated surfaces, such as door handles, elevator buttons, and water dispenser buttons;Inhalation of contaminated aerosols.To carry out the subsequent analysis more clearly, the SARS-CoV-2 transmission routes are classified into 6 types in this paper according to interpersonal distance and exposure way , includiNote that multiple routes of transmission may occur simultaneously. For example, in addition to direct contact, a handshake may involve a short-range airborne route, or even a large droplet route, if accompanied by a conversation. Positive samples for SARS-CoV-2 RNA can be detected in rooms with infected individuals, including in the air and on the surfaces of buildings and their personal belongings . AerosolThe virus distribution that was detected is due to a combination of droplet deposition and occupant touch. Liu et al.  exploredSpatial features can reflect individual attributes  and behavioral characteristics , thus potentially influencing the indoor infection process. Taking the school as an example, its functional space mainly includes classrooms, offices, dormitories, stairwells, corridors and lavatories. P-VV), and indirect influence on virus spread and viability through intervention in human behavior and IEQ. The plane layout not only determines the path and relative position of occupants, but also affects the airflow field of the room, thereby interfering with the probability and degree of human-to-human and human-to-object interaction (SL-BHH/BHO-VS), as well as the distribution of virus concentration in the air (SL-EA-VS), respectively. The touch-free design of public facilities helps reduce user contact with contaminated surfaces (SP-BHO-VS). Door and window openings determine indoor ventilation patterns  and thus affect the spread of virus-laden air (SO-EA-VS). In addition, the window configuration can change the temperature, humidity, and daylighting conditions in local areas of the room, thus affecting the stability of the virus (SO-ETRH/EL-VV).Although many studies deal with the impact of spatial factors on indoor environmental quality (IEQ) and occupant behavior, only a few studies are related to the relationship between viral spread and spatial parameters. Human-to-human transmission depends largely on people’s behaviors, especially when in close contact. The relative location to the infected person and gesture determines the manner of exposure. The details of respiratory activities and touching contaminated surfaces influence exposure levels, including exhalation and inhalation of virus particles and their transfer between contaminated surfaces, hands, and faces . A comprehensive understanding of human transmission-related behavior helps to assess the infection risk comprehensively and take corresponding preventive measures.The impact of spatial layout on occupant interactions is critical to the spread of COVID-19 in buildings. For example, spatial arrangements based on open-office concepts can enhance collaboration and communication among workers but increase the opportunities for virus transmission. A proper spatial organization has a redistribution effect on pedestrian flow, allowing people of different identities to move independently of each other, reducing route interference, and avoiding congestion-prone nodes. The effectiveness of the user’s experience of positioning and routing in a building is related to the familiarity of the space (relative to the role) and the complexity of the spatial organization. Most people tend to take the shortest route with the fewest changes in direction to their destination. A simpler spatial organization, that is, the shorter overall path length, exhibits a higher degree of human interaction . O’NeillAdditionally, the micro-pedestrian simulation in buildings can reproduce the walking behavior characteristics of people in real scenes based on pedestrian dynamics, thereby testing the effectiveness of different physical layouts. Pan et al.  investigThe arrangement of furniture, especially tables and chairs, determines the relative position of people when they sit for long periods , and is crucial to maintaining social distancing. For spaces with fixed seating , the number and spacing of tables and chairs represents the density, relative distance and the angle of the crowd . As showThe COVID-19 pandemic has brought unprecedented attention to touchless technology and has accelerated its development and use. In daily life and work, people inevitably touch certain private or public surfaces such as banknotes, doorknobs, and elevator buttons. Disinfection is required immediately after each contact, but this is difficult for most people to fully do. Touchless interaction technology is a new solution that can help reduce infection caused by exposure to fomites. Spatial openings generally refer to windows and doors, both of which are related to indoor-airflow organization caused by natural ventilation. The position of the window openings in the horizontal and vertical directions is the main factor affecting the airflow pattern, which is usually studied through field measurements and numerical simulations. Zhou et al.  investigThe size and shape of the window opening also have a significant influence. As shown in In addition, in the case of similar physical openings, the characteristics of incident wind and indoor airflow vary with the configuration of windows, which have been generally simplified to rectangular openings and have rarely been studied quantitatively . Figure In a multi-room building, the opening of the doors facilitates air convection and thus increases the ventilation rate of the room, which is thought to be effective in diluting contaminated air. As shown in Changing the physical layout at room level has been shown to cause changes in indoor-airflow fields, which, in turn, induce changes in ventilation effectiveness and distribution of pollutants in the air. Zhuang et al.  simulateAlthough SARS-CoV-2 RNA has been widely detected in the real environment, little has been said about the materials on exposed surfaces of spaces and facilities, which affect the stability of the virus on them. The viability of SARS-CoV-2 on different materials was mostly evaluated under laboratory conditions as shown in A few studies have examined the effect of antimicrobial coatings on SARS-CoV-2. Behzadinasab et al.  found thSpatial factors related to the inhomogeneity of indoor AT and RH include window openings and physical layout, which influence virus viability on surfaces and in the air ,105. TheIndoor AT and RH changes not only affect the evaporation and trajectory of virus-containing droplets , but alsThe above data are derived from limited laboratory experiments in which mechanistic models of viral decay kinetics were developed to predict the unobserved effects of AT and RH ,108. ManWindow orientation, WWR, window type  and shading devices determine daylighting quality, area, and duration , and solNumerous mathematical models have been developed to calculate the human infection risk ,121. WelSpatial factors have a great potential impact on the indoor virus transmission process, but these impacts have not been fully reflected in the assessment of indoor infection risk so far. There are several limitations to current studies on indoor COVID-19 risk assessment in considering the spatial factors: (1) First, the influence of building space factors on indoor infection risk is rarely discussed, and is mostly regarded as a “background” to analyse the effects of other factors such as behavior management, ventilation rate, etc.; (2) Second, most indoor infection risk assessment models do not integrate multiple transmission routes in the building space, but only focus on a single transmission route; (3) Third, the dynamic interaction between people and the environment were often oversimplified because the influence of spatial elements on occupant behavior is not taken into account. Therefore, we proposed a space-sensitive, multi-route infection-risk assessment framework , which iGiven the significant impact of spatial parameters on occupant behavior and virus transmission, an integrated 3D building model is the basis for simulating building-level COVID-19 outbreaks. The model contains detailed architectural space information, such as walls, doors, windows, tables and chairs, etc., which have specific material and touchable properties. In addition, the model includes indoor environmental information  from the integration of building spatial parameters and HVAC parameters.Since occupant behavior is influenced by the interaction of the body’s internal needs with the external environment, the occupant behavior model is based on individual characteristics and a detailed indoor-space model. As shown in Context-related behaviors include location, activity, movement route and duration, which are highly correlated with architectural spatial characteristics. The roles of occupants and their schedule of activities are determined according to the building type. Then, a dynamic grid of the spatiotemporal sequence of individual activities is established, which mainly includes two states: move and stay. A given stay state contains several activities and their durations, and a given move state contains the speed and path of movement based on purpose and context. In addition, multiple individuals in a space at the same time may exhibit some group-behavior characteristics (such as crowding and queuing) due to the intersection of paths. Taking a store as an example, the basic activity process of a customer includes entering the store, picking items, checking out, and leaving the store, and its arrival time, shopping duration and path are of great uncertainty. The basic activity process of a cashier includes arriving at the store, providing cashier services, and leaving the store, with a clear commute time and work schedule. There will be peaks in traffic at certain times, resulting in possible queues for customers to enter the store and check out.Extensive literature has discussed human activities observed in public spaces. Taking the office buildings as an example, sitting time usually accounts for more than 60%, standing time accounts for 10–20%, and stepping time is about 7–12% . The aveContagion-related behaviors are interactive behaviors performed by occupants in the process of moving and staying that promote the spread of the virus. It contains human-human interaction, human-object interaction, human-air interaction and self-inoculation. As shown in 1 and θ2 values of 0.Human-human interaction includes direct physical contact a–f and cHuman-air interaction refers to respiratory activity. Exhalation activities  include 2. Zhang et al. [Human-object interaction mainly involves touching inanimate surfaces, during which the virus is transferred between hands and surfaces. It is generally considered that the contact area of a finger is 1 cmg et al.  investigg et al. . The rigg et al. , as the Self-inoculation refers to the transfer of the virus by touching the facial membrane of susceptible individuals with contaminated hands , which iMicro-pedestrian models, such as social-force models, cellular automata models, and agent-based models, have been used to simulate individual context-related behavior and close human-to-human proximity to assess the effectiveness of policies regarding physical distancing . HoweverThe simulation of the spread of the virus is closely related to the movement status of the occupants. For droplet transmission and airborne transmission, some studies assume that all occupants remain stationary, and according to different research objectives, there are generally two considerations: (1) calculate the path of each droplet to restore the real conditions, and (2) assume that the droplets are uniformly distributed in the space immediately after being exhaled to simplify the calculation. The CFD technique allows for the tracking of detailed trajectories of droplets from being exhaled to landing or being suspended in the air and is widely applied in modeling the transport and distribution of virus particles . The LagIP (%) represents the infection probability, k is the number of virus species ingested and surviving in the host, r is the probability of a virus surviving in the body and causing an infection and N is the intake dose. This dose-response equation becomes an exponential equation through the simplification of the summation series:Calculating the risk of infection involves estimating the dosage received by an individual and then calculating the probability of infection under a given dose. The dose-response model allows for a more complete and accurate assessment of infection risk from the multi-route transmission, including droplet, airborne and contact transmission. When the distribution of the virus in the accessible medium follows the Poisson probability distribution, the dose-response model can be expressed as :(1)PI=∑kdcD, pfD, ldD, saD, efD, laD are cumulative exposure doses due to direct contact transmission, personal fomite transmission, large droplet transmission, short-range airborne transmission, environmental fomite transmission and long-range airborne transmission, respectively. tθ, dθ, iθ are the dose effects of touching the facial membranes, deposition in the upper respiratory tract, and direct inhalation, respectively.It reflects the interaction between the human body and the virus and the infectivity of the virus. When there are multiple transmission routes and the infectivity of the virus varies with the deposition site, the total infection risk through multi-route transmission can be calculated by Equation (3):The detailed spatial and temporal distributions of virus concentrations in the environment can help to obtain the intake dose for each transmission route. According to the proposed framework, the key issue for the co-simulation of 3D building models, occupant-behavior models and virus-diffusion models is the interaction of individual movement behavior data with CFD simulation data of droplet and aerosol diffusion. Yu et al.  transforThere are no studies yet to accomplish the ideal interaction of space, occupants and virus particles in one environment so far as we know. The agent-based model (ABM) can simulate the complex motion of multiple agents, and the bidirectional coupling with CFD has been realized in the field of biology. The occupants and viruses are regarded as dynamic agents, and the 3D architectural space is regarded as the activity environment of the agents. ABM can effectively describe the behavioral characteristics of environmental elements and agents and their micro-interactions, which provides an opportunity to couple the building-space model, the occupant-behavior model and the virus-transmission model.A hypothetical graduate student office is used as an example to illustrate the workflow of the framework , with a For the 3D building model, it is assumed that there are three forms of spatial organization: open, semi-open and closed and, in each case, there are three furniture layouts. Then a 3 × 3 layout matrix is generated. Moreover, the door handles, water dispenser switches and printer buttons in buildings are considered frequently touched surfaces. There are three optional materials for each surface, resulting in a 3 × 3 × 3 material matrix. A facility will not be considered in the environmental-contamination level calculation if its property is “touchless”. In addition, since most rooms in the building cannot be naturally ventilated, two types of mechanical ventilation (mixed ventilation (MV) and displacement ventilation (DV)) were chosen. Finally, a (3 × 3) × (3 × 3 × 3) × 2 matrix containing types of spatial factors is generated.1, n2, n3, and n4 agents, respectively. There are nine potential activities for each occupant during the day: arrival, lunch, departure, working, meeting, breaking, drinking coffee, going to the toilet, and printing, of which the last six activities can be considered as states of the Markov chain. Each role is assigned a basic activity schedule, based on which everyone makes minor adjustments to fit his habits. The route organization is generated by combining occupant-activity information with building information. The shortest path algorithm is selected assuming everyone is familiar with the office. At this stage, parameters such as the number of close contacts, average interpersonal distance, etc., will be used as indicators of high-risk behaviors in the space.For the occupant-behavior model, there are four roles in the office , each with nFor the virus-spread model, a random agent is selected as an infected individual, and the spread of the released virus can be calculated according to his/her activity network. The result is greatly affected by the role of the infected individual. The total exposure of the susceptible is the sum of the exposure from the air-based route and the surface-based route.For the infection risk prediction model, the dose-response model can be used to calculate the infection risk of a susceptible individual exposed by different transmission routes, and further predict the total infected population during building operation. In a complete workflow, the input parameters include the spatial factors of the office building, the occupant behavior features and the virus-spread data, and the output results consist of the spatial distribution of virus and agents, the occupant-exposure levels and the infection risk, etc.Given that most COVID-19 infections occur indoors, the whole process of RDs from release to ingestion was summarized in this paper, and the influencing factors involved were divided into three categories: space, environment, and behavior. This study highlights the role of spatial factors in individual infection-risk assessment, which include three aspects: spatial layout, public-facility design and opening design. They affected droplet-based, surface-based, and air-based transmission of the virus by intervening in occupant behavior and indoor airflow fields, respectively. In addition, changes in surface material and environmental factors  caused by opening design also have an impact on the virus viability.Most of the current research on the impact of spatial layout on occupant behavior is observational analysis, and the combined effect of multiple variables is difficult to predict. For example, a one-way space layout may not necessarily help reduce exposure risk, as the number of customers in a specific space decreases, their exposure time may increase. Spatial configuration and physical layout are complex issues in architectural design, especially for large public buildings. The detailed analysis of specific cases using space syntax can help to examine the effectiveness of spatial layout in reducing infection risk. Functional structure, circulation patterns, and horizontal and vertical accessibility are important factors affecting occupant distance and duration. Although the diversification of space functions is beneficial to space utilization, it is easy to cause the mixing of different groups and increase the probability of cross-infection. The multi-functional space is only allowed to undertake one function in a period through reasonable planning and management to avoid people from gathering at the same time. Enhanced spatial connectivity results in increased viral-diffusion efficiency, including the diffusion of contaminating gases and the spread of viruses on surfaces. The clearly structured circulation-pattern facilitates wayfinding and saves people unnecessary gathering time. While human-human and human-object interactions are primarily based on social relationships and schedules, their frequency and location preferences are still influenced by spatial configuration. Good visual connectivity increases unplanned interactions, such as open-plan offices for enhanced employee communication. Overall, it is easier to predict the impact of spatial factors on user movement and distance than the impact on interaction behavior.COVID-19 has helped us understand the importance of touchless infrastructure, but its contribution to reducing the risk of infection has not been quantified. Furthermore, the design and implementation of touchless products have two limitations: high economic cost and restricted accessibility for people with disabilities. But it is indisputable that touchless design will play an important role in building epidemic prevention and driving the development of smart buildings.2 levels to assess and control the indoor COVID-19 infection risk. In addition, Henriques et al. [The configuration of door and window openings includes location, size, and type, and its effect on the diffusion of contaminated air has generally been underestimated in previous studies. The effects of ventilation modes and ventilation rates on infection risk have been widely discussed over the past few years. José Luis Jiménez and his team evaluated parameters governing ventilation inside buildings  and vehis et al.  have estChanges in one space-design parameter may cause multiple reactions, such as the opening area of windows not only affects the diffusion of polluting gases and the virus viability, but also affects the thermal comfort of occupants and the energy consumption of buildings. The current research on building optimization focuses on comfort and energy efficiency, and standards for ventilation, temperature and humidity in public spaces also address indoor air quality and thermal comfort. The anti-epidemic performance of buildings is emphasized in this paper. For example, setting a minimum RH standard of 40% for public buildings will not only reduce the impact of COVID-19, but will also reduce the impact of further viral outbreaks, both seasonal and novel . GuideliTo calculate the comprehensive infection risk of indoor COVID-19, six possible transmission routes, as well as the spatial, environmental and behavioral factors involved are summarized. A spatially sensitive, multi-route risk-assessment framework is then proposed in this paper. The proposed framework helps building practitioners and managers to gain an overall perception of the risk of contagion in different building spaces, as well as the transmission routes that contribute the most, to propose targeted interventions. The framework required (1) to be able to control the detailed spatial and environmental parameters, (2) high-fidelity simulation of occupant context-related behavior and contagion-related behavior, (3) coupling the microscopic behavior model with the virus spread model and, (4) allowing for efficient computation and visualization.This work emphasizes the importance of complex space-human-virus interactions, of which three key issues are involved: (1) First, human-space interactions require detailed data to ensure high fidelity and randomness of behavioral simulations, which are different from those of single, generalized motion patterns. Microscopic behavior simulation has been extensively studied in the field of building safety and energy consumption. Context-related beha vioral data can be obtained experimentally ; yet, traditional observation and self-reporting fail to meet the accuracy and precision required for infection-related behaviors, especially respiratory activities and touch behaviors. Due to privacy and technological constraints, there is little data on occupant exposure habits. Only the surface touch network of office workers has been studied, but specific details such as contact area and friction remain unclear. (2) Second, space-virus interaction is related to the virus spread and survival, which has usually been ignored in previous studies. While 70% of virus particles in the air will be deposited on environmental surfaces, the spread of the virus to all surfaces in the space, this is rarely considered in the study of contact transmission. Most conclusions about the impact of surface material, ambient temperature and humidity and sunlight on the virus viability are based on laboratory measurements. More research is needed to obtain the viability of the virus in the real environment, which can be disturbed by a variety of factors. (3) Third, the dynamic interaction between space, humans and viruses requires coupling the microscopic behavior model and the virus-spread model and adding the obtained data to the infection-risk calculation model. Most of the current research only focuses on a single airborne or contact transmission. The co-simulation of CFD and ABM provides an opportunity to calculate the exposure dose of the virus for multi-path transmission. In addition, one of the other limitations in the COVID-19 infection risk assessment is the large inconsistency of the SARS-CoV-2-related virus data in calculating the exposure doses and infection risk. There are different opinions about the virus mortality rate, the size and number distribution of exhaled droplets, the viral load in the droplets, and the parameters in the dose-response formula.Our findings highlight the potential contribution of building-space design in the control of the spread of respiratory infectious diseases. The effectiveness of nonpharmacological interventions, such as increasing the air-change rate and the frequency of hand washing, and social distancing, was widely discussed. However, the effectiveness of possible spatial interventions has not been emphasized. The impact of single spatial measures requires further research, as well as the combined effect of multiple interventions. Effective control measures for a specific space should be proposed based on the characteristics of the occupants and their activities. As presented in the case study of the graduate student office, most agents work up to 8 h and their location changes frequently with roles and activities. Potentially effective interventions for the building include: (1) Spatial measures need to be implemented according to on-site ventilation conditions, population density, occupant behavior and spatial conditions. For example, dividing the office area into smaller units to avoid excessive crossing of routes and large-scale aerosol diffusion could be an effective measure under normal- or high- efficiency ventilation conditions ,94. HoweOne of the limitations is that although multiple transmission routes are considered in this article, there are still some potential or actual transmission routes not covered by this article, which, to our current knowledge, lack of sufficient evidence from cases and academic literature, such as the faecal-oral transmission and the vertical spread of virus-laden aerosols through stacks and vents. The lack of evidence is due to the fact that the detection and tracking of virus particles is limited by venues and technologies, and the sampling and handling of virus requires specialized and safety laboratories, which are not available to general researchers. Moreover, in real scenarios, multiple transmission routes appear in combination and cannot be completely distinguished. Once infection occurs, even if there is evidence of viral transmission, especially via the aerosol route, the spatial impact of individual infection is not easily demonstrated.This study reviews the multi-route transmission of SARS-CoV-2 in indoor spaces and investigates the spatial, environmental, and behavioral factors involved and their relationships. The spatial factors affecting the indoor virus spread include three aspects: spatial layout, public-facility design and opening design. This paper summarized the role of spatial factors during virus transmission, including affecting the movement of the virus by intervening in occupant behavior and indoor-airflow field and affecting the virus viability by changing the surface material and environmental conditions etc. Furthermore, a space-based, multi-route infection-risk assessment framework is proposed, aiming to build a big picture of indoor infection risk assessment, while helping to understand and analyse the effectiveness of different spatial, environmental and behavioral interventions more accurately. A graduate student office is used to explore the possibility of applying the framework. Our future work will focus on the data collection required in this framework to enable co-simulation of complex interactions between space, occupants, and viruses.


Background: While noma affects hundreds of thousands of children every year, taking their lives, disfiguring them and leaving them permanently disabled, the economic and social costs of the disease have not been previously estimated. An understanding of the nature and levels of these costs is much needed to formulate and implement strategies for the prevention and control of this disease, or to mitigate its burden. The objectives of our study were to develop a model for estimating the economic and social costs of noma and to provide estimates by applying this model to the specific contexts of two countries in the “noma belt”, namely Burkina Faso and Niger. Methods: Three main approaches were used. The estimation of prevalence levels of potential noma cases and of cases that should receive and actually do receive medical care was carried out using a literature review. The documentary approach made it possible to estimate the direct costs of noma by analyzing the database of a non-governmental organization operating in this field and present in both countries. Indirect costs were estimated using the human capital method and the cost component analysis technique. Results: The direct costs of care and management of noma survivors amount to approximately USD 30 million per year in Burkina Faso, compared to approximately USD 31 million in Niger. They mainly include costs for medical treatment, surgery, hospital stays, physiological care, psychological care, social assistance, schooling, vocational training and care abroad. Indirect costs are estimated at around 20 million in lost production costs in Burkina and around 16 million in Niger. Costs related to premature deaths are estimated at more than USD 3.5 billion in Burkina Faso and USD 3 billion in Niger. Finally, the costs to survivors who are unable to marry are around USD 13.4 million in Burkina and around USD 15 million in Niger. Intangible costs were not calculated. Conclusions: The neglect of noma and inaction in terms of prevention and control of the disease have enormous economic and social costs for households, communities and states. Future studies of this kind are necessary and useful to raise awareness and eradicate this disease, which impacts the health and well-being of children and results in lifelong suffering and severe economic and social costs to survivors and their families. With an estimated annual incidence of 140,000 cases worldwide, noma, more than any other disease, is a condition that, through its physical, psychological, and social repercussions, calls into question the capacity of societies and communities to protect children and young people from the threats associated with hunger, violence, and social inequality ,3,4. HowResearch to date has focused on the epidemiological, aetiological and clinical aspects, in particular reconstructive surgery and, more recently, on the prevention of the disease ,5,6. TheSimilarly, certain social consequences of noma are often mentioned but they have not yet been explored in depth. This is the case when it comes to the social exclusion and discrimination of direct and indirect (family or households members) survivors, for which the typology forms, mechanisms of expression and courses of action have not yet been studied ,8. HowevTo date, this entire set of economic and social costs associated with noma has not been the subject of specific studies. With a greater orientation towards political economics, the only publication linking noma to economics is a call for this disease to be used as an economic indicator of the “poverty” of the states where it occurs . SimilarUnderstanding the economic and social costs of noma raises a number of interesting issues. Firstly, it complements the arguments on which current control strategies are based. The only public health arguments generally highlighted are related to the burden of morbidity and mortality, and moral arguments are based on the fragility of children and society’s responsibility to give them the protection they need for their development or based on the rights of the child, on human rights and therefore on the obligations of states. However, those arguments do not seem to have produced the desired effects ,9,14,15.Secondly, better knowledge of the costs of noma could also provide a strong economic argument for programs to prevent the disease and support rehabilitation activities for survivors. Furthermore, this knowledge is necessary to combat certain religious, cultural or customary practices that severely limit women’s power, their access to the means of production and the administration of their property. These practices generate, maintain, reinforce and replicate the poverty of women and mothers, whereby the primary victims of such poverty are children, and noma is one of the associated diseases ,17.Finally, knowledge of these costs would facilitate broader social mobilization of the many local, national and international stakeholders involved in combating noma by widening the sphere of responsibility beyond the health sector. Certain United Nations agencies such as FAO, UNESCO, ILO, sub-regional organizations (ECOWAS) or regional organizations (AFRICAN UNION), or even financial development institutions (African Development Bank and World Bank), which are criticized for their apparent lack of efficacy, would thus find the necessary rationale for their involvement in the prevention and control of noma .Classified by the WHO as DAOC.31 in the International Classification of Diseases ICD-11 , noma seTechnically, the costs of illness or disability are divided into two broad categories according to Rice: (1) basic costs are those resulting directly from the illness and (2) other associated costs including those not related to the illness. Within each category, there are direct and indirect costs. Direct costs are those for which payments are made and indirect costs are those for which resources are lost. Indirect costs include (1) morbidity costs, the value of lost productivity of persons unable to perform their usual activities or perform at full efficiency due to illness; and (2) mortality costs, the value of lost productivity due to premature death, calculated as the present value of future benefits to society ,23.Noma, The Neglected Disease, An Interdisciplinary Exploration of Its Realities, Burden and Framing” carried out at the Institute of Global Health of the University of Geneva in collaboration with a number of academic partners, UN agencies, governmental entities and non-governmental organizations listed in the acknowledgements. It should be noted, however, that the views expressed in this study are not binding on these partners.Before describing the research methodology used, it is worth presenting the context in which this study was conducted. Institutionally, this work is part of the research project “Two countries were selected as part of the project’s research and served as a framework for observation, with their social, demographic and economic data being used to estimate the economic and social impact of noma. Both countries are known for having high levels of noma prevalence ,24,25 anThe two countries also have significant overall differences. The mean annual income was USD 790 for Burkina in 2019 compared to USD 590 for Niger in the same year according to World Bank data ,27. SomeAnother differential characteristic between the two countries relates to their rates of urbanization, which stood at 31% in Burkina compared to 17% in Niger in 2020 ,27. FinaThis situation is due to another common challenge faced by both countries, namely the deterioration of the security situation—more so in Burkina than in Niger—resulting from the actions of several jihadist groups including Boko Haram. Breaking down the number of attacks on the basis of the countries affected by the attacks, the joint report by NSDD-SHUB and ACRST  shows thThe objectives of this study were to develop a model for estimating the economic and social costs of noma and to provide estimates of these costs by applying this model to the specific contexts of the two countries presented above.The results of this study should make it possible to (i) provide decision-makers at various levels with basic tools for control strategies and for assigning the necessary resources to preventive measures and to the care and rehabilitation of noma survivors; (ii) incorporate economic and welfare concerns as a new dimension of noma research, prevention and control; and (iii) formulate proposals for better management of noma survivors in relation to the economic and social requirements of their rehabilitation.The estimation of the number of potential noma cases in these countries was based on (i) the scientific literature produced on the subject between 2003 and 2021  national sources namely the National Institute of Statistics and Demography of Burkina Faso and its counterpart in Niger, (ii) international sources such as the national offices of the United Nations Development Program (UNDP) and the World Bank.https://www.sentinelles.org/ (accessed on 22 November 2021), which has been developing prevention and care activities related to noma in Burkina Faso and Niger since 1992.The data on social and health expenditure for children with noma were found from the activity reports and a database of the Sentinelles Foundation The direct costs of noma include the social costs  for children with noma, as well as the direct costs of care, which include the costs of treatment, surgery, hospital stay, psychological management and physiotherapy in the country and the costs of transfer and care abroad.The costs arising from the loss of production due to the premature deaths of noma victims constitute the indirect costs. They are estimated by considering that the years of life lost as a result of such deaths or disabilities due to noma lead to productivity losses for individuals, households and states, according to the human capital approach ,43,44. TThe costs related to the stigma, discrimination and suffering of noma survivors constitute the category of intangible costs.Burkina Faso and Niger had 20,244,080 and 22,442,948 inhabitants, respectively, in 2018. Based on the estimate by Bello et al.  that nomFrom these two estimates, the numbers of potential noma cases were calculated based on the annual incidence rate of 6.4 cases per 1000 people as estimated by Fieger et al.  and agreFinally, as a third step, we deduced from the latter two estimates the numbers of potential noma cases receiving care or who should receive care, by taking the 10% of potential noma cases based on indications by Srour et al. . These aThe levels of life expectancy at birth 2018) used are 61.2 years and 62.0 years for Burkina and Niger, respectively, based on data from the Population Data website ,44. The  used areThe mean annual per capita income is USD 750 for Burkina Faso and USD 570 for Niger in 2018, according to World Bank data .These results are summarized in The direct costs of care and management of noma survivors calculated on the basis of data provided by the Sentinelles Foundation amount to approximately USD 30  million per year (2018) in Burkina Faso, compared to approximately USD 31  million in Niger. They include 48% of care and social assistance costs and 52% of costs related to care abroad for under 200 (172) people in Burkina Faso. The results for Niger are divided along similar lines. The major cost drivers are—in order of importance—hospital or health center stay , medical care , surgery , physiotherapy  and assistance with income-generating activities  in Burkina Faso. This order of importance is almost identical for Niger.In this category of direct costs, the most important item is the cost of surgical transfers abroad, estimated at USD 85,000 per case in 2020 according to data provided by the Sentinelles Foundation, and, for the 172 and 185 potential transfer cases, these costs are around USD 15 million  and USD 16 million  for Burkina Faso and Niger, respectively.Calculated based on potential cases of noma in persons of legal working age (15–29 years) and mean annual incomes of USD 750 and USD 570 for the two countries, the indirect costs of lost production are around USD 20 million  for Burkina and over USD 15 million  for Niger for the year of the study.In this same category, the costs related to premature death  were calculated by taking into account the number of potential noma-related deaths (90%) of potential cases , the mean annual income (USD 750 and 570) and the years of life saved (55.2 and 56.0 years). The estimates reached are USD 3,562,428,600 for Burkina and USD 3,041,082,240 for Niger, which corresponds to the highest cost by far.being unable to marry by noma women survivors, i.e., their inability to marry or the difficulties they face when it comes to marrying. When women are not able to marry, the absence of dowry can be considered an economic burden for their families. The number of women of marriageable age (15–29) among potential noma cases and the average costs (dowry and related expenses) of marriage estimated at USD 1000 in both countries by two independent informants were taken into account. These costs are therefore USD 13,365,000 in Burkina and USD 14,820,000 in Niger.Finally, we calculated the costs of The intangible costs of pain, suffering, stigma and discrimination are difficult to estimate and have not been calculated.These results are presented in detail in The objective of this study was to calculate the economic and social costs based on a model previously developed and applied to the contexts of two countries in the “noma belt” (Burkina Faso and Niger). Although this is the first study of its kind for this disease, the level of direct costs, particularly those of medical care , averaged USD 1829 per case in both countries, a figure close to the USD 1,791.7 direct costs of care for a case of a condition sometimes confused with noma, Buruli ulcer, in Benin . This saThe report on mean annual income does not include the significant disparities across these countries. Families living in extreme poverty have never seen this annual income. Their lack of income is not reflected in the mean annual per capita income. Their level of poverty is often not recorded.The estimated cost levels depend not only on known socio-demographic indicators but also on the estimated prevalence of noma cases. However, there are several factors that limit the validity of incidence levels from various sources. Firstly, incidence rates vary enormously between studies; from 8.3 per 100,000 persons at risk in Northwest Nigeria to 7 per 1000 children aged 1–16 years in the same country ,52.Next, the 1998 WHO estimate of 140,000 new cases of noma per year seems to have been greatly exceeded more than a quarter of a century later due to (i) the deterioration of the security situation in the region; (ii) the effects of the 1994 devaluation of the West African CFA franc on the standard of living of the population; (iii) and the consequences of climate change on agricultural production. Associated with noma, the rates of acute malnutrition, chronic malnutrition and low body weight at a national level were 9.1% (of which 1.0% in the severe form); 24.9% and 17.6% in December 2020, and only 21.9% of children in Burkina Faso have a minimum acceptable diet .Finally, it should be remembered that most studies on the epidemiology of noma are based on hospital data, leading some to suggest that these estimates may not accurately reflect the actual incidence of acute noma or the prevalence of patients with noma sequelae, as they are based on expert opinion or historical data. It is also not known which stages of noma are included in these estimates ,34. It iOther social and economic costs of noma have not been included in our study. These include pre-hospital care or costs resulting from the use of traditional and alternative medicines. It is known that about 80% of the population in this region uses traditional medicine, and, in Niger, 40% of children suffering from noma were first seen by a traditional practitioner . ResultsIn the same vein, the reader will note that the costs of noma prevention programs and activities have not been calculated. This should not be interpreted as a complete absence of such activities in the countries where noma occurs and during the period covered by the study. It is due to the impossibility of identifying such activities at the central, state, or regional level by the various national or international organizations directly involved in the fight against noma or those organizations operating in related areas, such as in the field of nutrition.In this area, a study reporting on the intervention of Médecins sans Frontières in the prevention of malnutrition in Niger indicates that approximately USD 59 had been distributed to households in addition to food distribution between August and December 2021. This amount is not only recommended by the government but is also practiced by other international organizations .Finally, the funeral costs often borne by households and communities were not included in our study. Nevertheless, they are known to be high and deserve to be incorporated into future estimates. For the two countries considered, total funeral costs following deaths due to poor sanitation were estimated at USD 130 million in 2012 in Niger and USD 150 million in Burkina Faso by the World Bank’s Water and Sanitation Program .Even without including pre-hospital costs, costs of prevention activities or costs of funerals in both countries, the estimated direct costs represent a huge burden for households, communities, states and other local or international stakeholders. The direct costs of caring for noma victims represent about half of the costs of social sector staff in Burkina in 2014—about 39 billion CFA francs—and would cover the mean nationwide health expenditure of one million people in Niger in 2016 ,58.The costs of schooling for each child with noma were calculated on the basis of USD 175 from the Sentinelles Foundation data. This figure is not so far from the estimate provided by specialist sources in the sector, indicating that the household contribution to pre-school education expenditure would be around USD 140 in Niger in 2020 . Using tHowever, it should be remembered that these costs may be underestimated or overestimated due to a double effect on the prevalence of school-age children with noma, which may be lower in the younger age groups (0–6 years) on the one hand, and in adolescents and adults with noma, who are inside or outside the education system.The indirect costs are the highest. Those related to lost production, estimated at USD 16 million, represent half of the costs of implementing free healthcare measures, estimated at 20 billion XOF during 2016 in Burkina Faso  . The cosOne question that arises at this point is: which institutions or structures should absorb these costs, i.e., who should pay for them? In the case of noma, as with other health problems, it is known that it is the households  that cover these expenses. On this subject, Kouyate et al. point out that, in Burkina Faso, the state and external aid, respectively, cover 18% and 28% of all health expenditure and that the remaining 54% is financed by the population . These pIn this context, it should be stressed that the (non-funding or) under-funding of prevention, care and rehabilitation activities for noma survivors is an undeniable fact. The denial of the prevalence of this disease by certain states, the stigmatization and discrimination affecting people with the disease and their families, the refusal of care by some parents, ignorance of the disease, including by traditional practitioners and health professionals in the modern medicine sector, and the fact that this disease is not included in the list of neglected tropical diseases constitute the major obstacles to the financing of projects and programs for the care of noma ,60. As aThis underfinancing or non-financing of the fight against noma leads not only to the levels of costs estimated above but also to additional costs associated with their increase. These are, in effect, the costs of inaction—which may be seen as the overall social and economic costs of the failure to invest in combating this disease. Inaction, or preserving the status quo, impacts individuals and on economic and social structures in the long term. Such costs seem not only unjustified, but also unacceptable.This inaction is itself a corollary of the recognition of the existence and prevalence of noma in the affected countries, and also of the commitment of the states concerned to address it. This recognition and commitment varies enormously between states. In Africa, where noma was declared a health priority in 2006 , some stAs can be seen, the levels of economic and social costs of noma depend on the economic, social, legal and cultural context of each country on the one hand, and on the state of the health system and security environment on the other. Estimates of these costs should consider these contexts by avoiding a mimetic application of the estimation model presented in this study.As the first study, to our knowledge, to develop and test a model for estimating the costs of noma in the research into the condition, our study has some obvious strengths. Firstly, the estimation model used is an adaptation of an earlier concept that has proven its validity in estimating the social and economic costs of one of the most serious forms of human rights abuse, namely torture. Secondly, the direct cost values used are actual data from an organization that has been working on noma for many years. The estimated direct costs were therefore closer to those known from the context of medical care for other types of diseases as mentioned above, thus proving the external validity of our results. Finally, the study is based on the authors’ actual knowledge of the contexts of the two countries as well as the support of local networks and expertise used in this research.However, these strengths cannot hide certain limitations, some of which have already been mentioned. The first limitation concerns the existence of cost categories that were not estimated in our study. These include the costs of preventive activities or those arising from pre-hospital care. The second limitation is that most of the data used come from the database of a single non-governmental organization. These data are a function of the organization of this structure, i.e., its choices, resources and cardinal values in the provision of care and/or social assistance. Third, the estimated costs may increase quickly, and lose representativeness. Finally, the present cost estimates rely on incidence and prevalence estimates from studies with a very small number of cases. Thus, they are indicative but might be underestimated.Furthermore, the level of costs associated with care abroad may appear high to some. The patient transfers and the care in question took place in Switzerland, which has some of the most expensive living standards and healthcare costs in the world. Switzerland is ranked as the 2nd most expensive country in the world after Bermuda, while France is ranked 19th and Italy 32nd according to the Numbeo Quality of Life Index and other authors . These cPart of this discussion focused on the difficulties of determining the incidence rate of this disease and estimates of prevalence levels for potential populations at risk of noma and of those receiving treatment or who should receive treatment. In the absence of consensus on this issue, studies on the burden of this disease will suffer from this shortcoming.An apparent “gap” in research on noma, with the majority of work devoted to West Africa in general and to the countries belonging to the “noma belt” in particular;A predominance of clinical studies in the epidemiology of noma, with a critical lack of population-based studies, even though these are necessary to understand the extent of the condition;An apparent dearth of studies on the role and importance of social structures both in the emergence of noma and in the strategies to combat it;A lack of knowledge of the disease among health professionals, including traditional healers ,36,63;However, this shortcoming is by no means the only reason why new research on noma in general, and on its economic and social costs in particular, is needed. This field of research is characterized in particular by:Widening the scope of research to include states where prevalence levels are not known and where there are no health data on the subject in existence;Testing the proposed noma cost estimation model by applying it to different contexts and different health and social systems;Orienting cost studies towards understanding the distribution of costs by paying agent ;Incorporating social sciences, in particular, political economics, sociology, history, anthropology, political epidemiology and human rights into the research and activities to combat noma;Encouraging and educating states that are already committed, not very committed or still in denial to invest in the prevention and fight against noma, thus avoiding the enormous costs of their inaction;Training health professionals, including traditional practitioners, in the diagnosis and care of people with noma and in the collection, management and use of social and health data on noma cases occurring in the community or received in consultation;Sharing good practices in prevention and care, and in the rehabilitation of noma survivors;Aiming in the long term at completely eradicating this disease of shame and collective irresponsibility towards our children.In view of this situation, new perspectives for research and action should focus on:This study aimed to design a model for estimating the economic and social costs of noma and to apply it to the specific contexts of two African countries: Niger and Burkina Faso. These objectives were achieved through efforts to conceptualize and categorize the costs on the one hand, and to identify and collect data on the socio-demographic indicators necessary for this estimation on the other.The foundations for estimating the economic and social costs of noma have thus been laid. They constitute a call for the continuation of such studies, taking into account the different political, demographic, economic and security contexts, as well as the different health and social systems.The failure of governments to invest in the prevention and control of noma has and will continue to have enormous costs for households, communities, states and the children themselves in the long term.Analysis and understanding of both the causes and the structural effects of noma are necessary steps for such investments. Achieving them is our shared responsibility.


Mollusca is one of the largest phyla in the animal kingdom that includes more than 100,000 existing species living in aquatic and terrestrial habitats. Within this phylum, marine molluscs are considered an important resource for fisheries, and gastropods represent 2% of marine molluscs fished worldwide. Similar to bivalves, gastropods are susceptible to environmental contamination, and they are able to accumulate microorganisms. However, despite their economic importance, only few studies have focused on the monitoring of viral contamination in their tissues and their possible role as carriers. In this study, the presence of human pathogenic viruses such as hepatitis A virus, but not noroviruses, different to the situation in bivalve molluscs, was found in gastropods. This finding suggests a low risk of food-borne viral infections for gastropod consumers. Furthermore, one of the most impactful pathogens for marine aquaculture, nervous necrosis virus (NNV), was detected in gastropods. However, the animal tissues examined did not show any histological changes, suggesting the absence of a pathogenic effect of NNV in the analyzed gastropods.Tritia mutabilis, Bolinus brandaris and Rapana venosa) collected during the fishing season from 2017 to 2021 in the north-western Adriatic Sea, and on clams (Ruditapes philippinarum) harvested in the same geographical area, in order to evaluate the presence of human and fish viruses in their tissues. A virological investigation was carried out on the digestive gland using molecular methods. The presence of hepatitis A virus was detected in one sample, whereas noroviruses were not present in the investigated specimens. Regarding fish viruses, it was possible to detect the presence of nervous necrosis virus (NNV) in 26.5% of the analyzed gastropods; however, the histological examination did not show any pathological changes in the nervous tissue in both NNV-positive and -negative batches. As a whole, the investigated gastropods showed the ability to bioaccumulate viruses; however, lower contamination by human viruses compared to bivalve molluscs was pointed out, posing a minor concern to human health.Marine gastropods represent a major food source for higher trophic levels and an important source of animal protein for humans. Like bivalve molluscs, gastropods can accumulate several types of contaminants; however, the bioaccumulation of microorganisms, particularly viruses, has been poorly investigated in these animals. This study focused on gastropods ( Gastropoda is the most diverse molluscan class that includes more than 75,000 existing species. Gastropods are highly abundant in marine ecosystems, playing an important ecological role as grazers, scavengers and predators. They also represent a major food source for higher trophic levels .Tritia mutabilis, represent an important resource of local income for small-scale fisheries in the Adriatic Sea [Furthermore, marine gastropods are an important source of animal protein for humans , and somatic Sea .Similar to bivalves, gastropods are very susceptible to environmental contaminants and have been shown to accumulate metals and marine biotoxins . FurtherBecause of their ability to bioaccumulate microorganisms, these species may play an important role in the transmission of human pathogenic viruses such as noroviruses (NoVs) and hepatitis A virus (HAV) .Norovirus, family Caliciviridae. These viruses are genetically variable and classified into 10 genogroups (GI-GX), among which NoV GI and GII represent those most frequently associated with human infections [NoVs are non-enveloped viruses belonging to the genus fections .Hepatovirus, family Picornaviridae. Human HAVs are divided into three genotypes  and seven subgenotypes , of which the subtypes IA, IB and IIIA are responsible for the majority of human infections [Hepatitis A virus (HAV) belongs to the genus fections .Umbonium giganteum) [n = 27) of sea snails collected in Japan during a period of five months [The role of marine gastropods in the accumulation and spread of human pathogenic viruses has been poorly investigated. An acute gastroenteritis outbreak associated with norovirus and sapovirus occurred in 2011 in Japan in subjects who had consumed raw sea snails (ganteum) . FurtherBetanodavirus, family Nodaviridae, and it is responsible for viral nervous necrosis, a disease that causes severe mortality outbreaks with nervous clinical signs in several marine fish species [Recently, it was evidenced that bivalve molluscs are able to accumulate fish viruses such as nervous necrosis virus (NNV). This virus belongs to the genus  species . Betanod species . Bivalve species . Moreove species .Stramonita haemastoma) belonging to the Muricidae family [Betanodaviruses are reported in a growing number of other invertebrate species such as cephalopods ,13 and ge family .T. mutabilis, in order to promote this important product for small-scale fisheries. Furthermore, the investigation on pathogenic viruses of aquatic animals was conducted to increase the surveillance of one of the most threatening pathogens for finfish species of the Mediterranean Sea and to evaluate the possible involvement of gastropods in the epidemiology of viral nervous necrosis.As part of the project PO FEAMP ITALIA 2014–2020 “Pilot action for the sustainability of small-scale fishery in Emilia-Romagna Region”, an investigation was conducted to assess the presence of human and fish viruses in gastropods collected in the Adriatic Sea. In particular, the survey focused on T. mutabilis, 6 batches of Bolinus brandaris and 1 batch of Rapana venosa were analyzed.A virological investigation was conducted on 34 batches of marine gastropods collected during the fishing season (October–May) from 2017 to 2021 on the Emilia Romagna coast. Gastropods were collected by fishermen using basket traps according to the small-scale fishery operations usually conducted in the Adriatic Sea . In particular, 27 batches of A molecular investigation was conducted to determine the absence/presence of 4 viruses: norovirus GI (NoV GI), norovirus GII (NoV GII), hepatitis A virus (HAV) and nervous necrosis virus (NNV).Ruditapes philippinarum) collected in the north-western Adriatic Sea from 2017 to 2021.Furthermore, for comparison purposes, a virological investigation on human pathogens was also conducted on 54 batches of Manila clam  following the manufacturer’s instructions. The investigation on the presence of viral RNA was conducted using specific and previously optimized protocols.Digestive gland homogenates were subjected to viral RNA purification using the protease K method ,16. BrieIn particular, the presence of HAV was assessed through an RT-nested PCR assay targeting a VP1 fragment performed according to a method previously described .The presence of noroviruses was evaluated using two real-time RT-PCR assays that enable a qualitative detection of NoV GI and NoV GII .Regarding nervous necrosis virus, its presence was investigated in gastropods using an RT-nested PCR assay targeting the viral RNA1 segment . Furtherwww.ncbi.nlm.nih.gov accessed on 2 February 2022), to confirm the viral identity.Amplicons obtained from these reactions were visualized through gel electrophoresis and then purified from agarose gel  or from PCR products . Then, they were quantified through a fluorometer  and sequenced with specific primers . The obtained sequences were manually corrected and analyzed through the online program Basic Local Alignment Search Tool (BLAST), available on the National Centre for Biotechnology Information site . The alignment was conducted using the Clustal W method implemented in the BioEdit software (http://bioedit.software.informer.com/ accessed on 2 February 2022). Neighbor-joining phylogenetic analysis of the partial VP1 gene was performed with MEGA X software (www.megasoftware.net accessed on 2 February 2022). Bootstrap analysis was carried out on 1000 replicates. The genotyping of NoVs was conducted using the Norovirus Typing Tool Version 2.0 [To further characterize the HAV strain found in gastropods and bivalve molluscs, a phylogenetic analysis on the partial gene of the VP1 protein was conducted comparing the obtained sequences with those of the HAV reference strain HM-145 and of a selection of Italian HAV strains  availablsion 2.0  by analyhttps://www.ncbi.nlm.nih.gov/genbank/ accessed on 26 April 2022) using Clustal W implemented in the BioEdit software (http://bioedit.software.informer.com/ accessed on 26 April 2022). The phylogenetic analysis was conducted using the maximum likelihood algorithm applied to partial RNA1 and RNA2 sequences with MEGA X software (www.megasoftware.net accessed on 26 April 2022). Bootstrap analysis was carried out on 1000 replicates.Regarding NNV strains found in gastropods, which have a bi-segmented RNA genome, a phylogenetic analysis was performed using both RNA1 and RNA2 gene fragments of the virus. The sequences of the detected viruses were aligned and compared with NNV sequences identified in both marine vertebrates and invertebrates as well as with betanodavirus reference strains available in GenBank  [Fourteen batches of anol 1%) . Then, tanol 1%) . Before T. mutabilis . Furthermore, 3 bivalve mollusc samples (collected in 2017 and 2019) out of 54 resulted in being positive for HAV, representing 5.6% of the R. philippinarum samples (Hepatitis A virus was detected in 1 sample (collected in 2020) out of 27 of  samples . SequencThe viral strain of HAV detected in gastropods belonged to subtype IA , whereasRegarding NoV, its presence was not detected in any of the tested gastropod samples. Contrariwise, the presence of NoV was shown in 19 out of 54 clam samples 35.2%; . In partB. brandaris and 5 samples of T. mutabilis , specifically in 4 specimens of utabilis . SequencThe analysis of NNVs’ genome allowed us to determine the viral genotypes. Both RNA1 and RNA2 sequences of all detected NNVs clustered with the RGNNV reference strain , showingT. mutabilis did not show histological changes. In particular, regarding ganglia, no degenerative changes  were detected in neurons and in fiber bundles of NNV-positive and -negative animals  or a complete absence of this virus [The presence of human viruses in aquatic gastropods has been poorly investigated hitherto; however, some studies pointed out the presence of human enteric viruses in freshwater and marine gastropods ,34. In pis virus ,36,37. Ais virus . The viris virus . In bivaOn the contrary, no presence of NoV was detected in any of the tested gastropod samples, whereas the presence of this virus was observed in 37.4% of clams, with a higher prevalence of NoV GII (85% of the positive samples) than NoV GI (15% of the positive samples). The result obtained in clams is in accordance with previous investigations conducted on bivalve molluscs sampled in the Adriatic Sea, which have already shown high prevalence values for NoV (22–51.4%) ,35,38. SDespite the fact that gastropods are not filter feeders like bivalve molluscs, the present study and a few previous reports ,34 showeT. mutabilis and B. brandaris. The analysis of NNVs’ genome showed that all the detected NNVs clustered with the RGNNV genotype, the most widespread in the Mediterranean Sea; no reassortant strains were detected in the gastropods.Regarding fish viruses, this study pointed out a frequent presence of NNV in gastropods of both species Despite the fact that RGNNV is a well-known finfish pathogen, its presence in invertebrates has been frequently reported too. In particular, it has been identified in several species of bivalve molluscs ,11,41, cRecently, RGNNV presence was also reported in one gastropod in Greece ; howeverThe presence of RGNNV in gastropods in our study was quite high, with 26.5% of the batches being positive for the virus. Similar contamination levels have already been observed in bivalve molluscs. In particular, a study conducted on commercial bivalve molluscs showed an NNV contamination rate of 26.3% of the tested samples including clams, mussels and oysters , with hiViruses from a number of families have been reported in gastropods such as Herpesvirusae, Bacilladnaviridae, Circoviridae, Reoviridae, Picornaviridae, Caliciviridae, Paramyxoviridae and Rhabdoviridae ,46; howeNodaviruses are neurotropic viruses generally associated with necrosis and vacuolar degeneration in both vertebrates and invertebrates ,48. In pT. mutabilis neurons and nerve bundles, constituting the visceral ganglia, and those belonging to the retina, did not reveal signs of alteration. In particular, the typical pathological signs were not present. The absence of degenerative changes in the neurons of NNV-positive gastropods suggests that these animals are capable of accumulating the virus without displaying signs of cell suffering. Despite the fact that we cannot exclude viral replication activity in the investigated tissues, RGNNV does not seem to induce pathologic effects in NNV-positive gastropods.The histological investigation, focused on the evaluation of T. mutabilis, confirming the ability of the gastropod to accumulate human viruses. Despite that, the low presence of these viruses in gastropods, compared to bivalve molluscs, along with the typical habit to serve this food well-cooked, suggests a low risk of food-borne viral infections for gastropod consumers.The presence of both human and fish viruses was found in gastropods. In particular, RGNNV was found in a reasonably high number of batches, similar to what has already been shown in bivalve molluscs. However, the histological investigation did not show any alterations in the nervous tissue, which is usually targeted by RGNNV in susceptible hosts, suggesting a low pathogenicity, or lack thereof, of this virus in gastropods. Furthermore, HAV was detected in one batch of


Diffuse Low-grade gliomas  are a heterogenous group of tumors comprising 13–16% of glial tumors. While maximal safe resection is endorsed as the best approach to DLGG, compared to more conservative interventions like stereotactic biopsy, the added costs and risks have not been systematically evaluated. The purpose of this study was to better understand the complication rates and costs associated with each intervention.International Classification of Diseases, Ninth Revision (ICD-9) codes corresponding to DLGG (2005–2014). Current Procedure Terminology, 4th Edition (CPT-4) codes were used to differentiate resection and biopsy cohorts. Inverse weighting by the propensity score was used to balance baseline potential confounders . Complication rates, hospital mortality, readmission, and costs were compared between groups.A retrospective cohort study using data from the IBM Watson Health MarketScan® Commercial Claims and Encounters database was conducted, using the p < 0.05). However, this association became non-significant after inverse propensity weighting . There was no statistically significant difference in unadjusted, 30-day hospital mortality (p = 0.06) or re-admission (p = 0.52). Resection was associated with higher 90-day total costs (p < 0.0001) and drug costs (p < 0.0001). Biopsy was associated with greater index procedure costs (p < 0.0001). Long-term outcomes and evaluation of DLGG subtypes was not possible given limitations in the metrics recorded in MarketScan and lack of specificity in the ICD coding system.We identified 5,784 and 3,635 patients undergoing resection and biopsy, respectively, for initial DLGG management. Resection was associated with greater 30-day complications (29.17% vs. 26.34%; Resection was not associated with an increase in the adjusted complication rate after balancing for baseline prognostic factors. Total costs and drug costs were higher with resection of DLGG, but the index procedure costs were higher for biopsy. This data should help to facilitate prospective health economic analyses in the future to understand the cost-effectiveness, and impact on quality of life, for DLGG interventions. However, the use of large national databases for studying long-term outcomes in DLGG management should be discouraged until there is greater specificity in the ICD coding system for DLGG subtypes. Diffuse low-grade gliomas  are a heterogeneous group of tumors that comprise 13%–16% of glial tumors . HoweverStereotactic biopsy was a more conservative approach that could obtain tissue for a histological and molecular diagnosis while minimizing the potential complications associated with upfront resection. Today, there is sufficient evidence to support maximal safe resection (MSR) as the best initial approach when feasible, to delay malignant progression and improve overall survival (OS) –12, indeFurthermore, it is important to also evaluate the health economic impact of each procedure as well. The survival benefit with resection may be associated with a greater risk of neurological sequelae  and addeEligible patients were identified from the IBM Watson Health MarketScan® Commercial Claims and Encounters database from January 2005 to December 2014. Our date cut-off was selected based on the transition from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) to the 10th revision, which occurred in 2015. This avoids potentially confounding our data by including two different iterations of the classification system. The MarketScan database contains all claims, paid and adjudicated, at an individual-level for those enrolled in employer-sponsored health plans . This daThis study was approved by the institutional review board at the Penn State Milton S. Hershey Medical Center. Informed consent was not required since all data was deidentified prior to access.Patients over the age of 18 years undergoing stereotactic biopsy or resection for a DLGG were included in this analysis . A diagnThe Charleston Comorbidity Index (CCI) was used to identify the presence and severity of comorbid conditions as a marker for complication risk at baseline. This variable was chosen because previous MarketScan database studies have validated its use. Furthermore, other brain tumor specific indices such as the Pignatti  and SawaAdverse events potentially attributable to the surgical intervention or post-operative course were identified with ICD-9 codes . All advRegarding costs, the total payments made by the individual or a third-party payer were used. All costs were adjusted to 2014 dollars using the United State Department of Lar Medical Care Consumer Price Index . A list Raw data are presented using descriptive statistics. Continuous variables are presented using mean and standard deviation. Dichotomous data are presented as frequencies and percentages. Univariate analysis was performed to assess statistical significance of differences in proportions using a Chi-Square test for categorical variables and t-test for continuous variables.The level of accepting statistical significance was set at 0.05, except for the individual complications, which were set to 0.004. We chose to adjust for multiple variables using the Bonferroni correction in this case to account for the analysis of 14 dependent variables (0.05/14 = 0.004). Multivariable analysis was conducted using logistic regression to assess the association between procedures (resection & biopsy) and complications, mortality, and readmission, respectively. Stereotactic biopsy was used as the reference when calculating adjusted odds ratios (OR).To further test the robustness of our results, we conducted a sensitivity analysis inverse weighted by the propensity score  to balanp < 0.0001 for both). The mean (SD) age was 46.0 (12.9) and 47.8 (11.5) years for resection and biopsy groups, respectively (p < 0.0001). The biopsy group had more patients in all age ranges except the youngest group (18–34 years). There were significantly more patients in the resection group that had seizures prior to their operation . Lastly, more patients in the resection group had CCI scores of 0 (26.04% vs. 37.80%) or 1 (7.87% vs. 13.67%), whereas the biopsy group had more patients with scores greater than or equal to 2 (66.10% vs. 48.53%) .We identified 5,784 patients undergoing resection and 3,635 undergoing biopsy for initial DLGG management . Baselinp = 0.0456) (p = 0.10). There was no significant difference in 30-day re-admission rates  or hospital mortality . The rates of each individual complication are shown in After excluding those with a complication code prior to surgery, there were 4,094 total patients remaining, of which 1,144 (27.94%) had a complication code post-operatively. Resection was associated with a higher rate of overall complications compared to biopsy  . Howeverp < 0.0001) and 90-day drug costs . Similarly, resection was also associated with higher out-of-pocket expenses for total 90-day costs  and 90-day drug costs ($210.84 vs. $153.61) (p < 0.0001 for both). Biopsy was associated with higher index procedure costs . However, there was no difference between groups for out-of-pocket expenses for the index procedure .Cost data are summarized in p = 0.97). For anti-epileptic drugs, the resection group had significantly greater costs compared to biopsy . These relationships remained the same when comparing out-of-pocket expenses alone.Lastly, we evaluated chemotherapy and anti-epileptic drug costs specifically . We founThere is now a wealth of evidence to support maximal safe resection as the best initial strategy for improving survival and delaying malignant progression . As we pGroups were balanced by comorbid conditions through our propensity score analysis, as well as geographic region and year in order to control for potential temporal or geographical influences on surgical practice patterns . Upon baThere was also no associated increase in re-admission rates or differences in mortality. Mortality has been considered low for both resection and biopsy, but can be estimated to be around 1.5%  and 0.9%via codes submitted by healthcare providers. Therefore, patients who die at home may not have their mortality data collected, nor would those who lost private insurance, such as those who became uninsured or transitioned to Medicare/Medicaid without supplemental private insurance.Although short-term outcomes were sufficient to evaluate the immediate post-operative complications associated with each procedures, we were unable to collect long-term outcomes as part any secondary analyses. Theoretically, these could be evaluated, but we felt this data would be unreliable given how MarketScan collects this information. MarketScan will only collect data on those who possess private health insurance, and this data is collected Regarding cost, we found that resection had higher 90-day total and drug costs, including the out-of-pocket values for each. This difference was not attributable to chemotherapy drug costs, as these were similar in both cohorts. However, anti-epileptic drug costs were higher in the resection cohort, which may represent increased seizure severity in this group. To assess all costs more accurately, including tangible and intangible ones, prospective health economic analyses that take into consideration the patient perspective with appropriate time horizons are necessary.The overall index procedure costs were higher for biopsy, but the difference in out-of-pocket expenses for the index procedure was not statistically significant between groups. These are the costs incurred on the same date as the initial resection or biopsy procedure itself. Further research is needed into why these costs were higher for biopsy when no others were. It may have to do with facility costs or other administrative costs that are higher for biopsy, such as charges that do not end up being seen by the patient given that index procedure cost was not significantly different from resection when looking at “out-of-pocket” costs alone. Biopsy procedures likely have more disposable medical equipment involved. In addition, stereotactic biopsy equipment is expensive, and this may be transmitted into higher cost to the healthcare system on the day of the procedure, which is absorbed by the hospital and not seen by the patient. Given that this cost does not include post-operative care, it is not altered by post-operative complications, which may have contributed to the higher 90-day costs for resection. Biopsy is a more cost-effective procedure in the treatment of many tumors , but ourThere is a scarcity of research regarding cost-effectiveness for DLGG management . Due to Some of these limitations are inherent to any study using an administrative claims database. Given the retrospective nature of these analyses, we are limited to the predetermined variables collected by the database and the information defined by each clinical code. Regarding our findings, we were unable to include all known or potential prognostic markers related to DLGG management, which play a role in the decision-making process when determining the best surgical approach. In addition, we were unable to assess the severity of each complication. Our cohort included only those patients with commercial health insurance and therefore these results may not be generalizable to all patient populations, but it should be noted that the MarketScan population is representative of the largest segment of American healthcare users.However, we also recognized specific limitations in using large administrative databases for studying DLGG. First, long-term outcomes were not able to be assessed. Although there was sufficient data to evaluate our objectives in the immediate post-operative period, it prohibits the use of these databases for extended outcomes that are important for slowly progressive diseases like DLGG. For example, many patients will be treated with chemotherapy longer than the 3 months analyzed here and although we may be able to extrapolate our results to the full treatment duration, it would be ideal to expand the length of data collection to capture all chemotherapy cycles.via the ICD coding system, which is an imperfect method for properly classifying intracranial tumors. First, this code encompasses also encompasses benign tumors such as grade I gliomas, ependymomas, choroid plexus papillomas, and dermoid/epidermoid cysts. We believe that we excluded many of these entities by only including supratentorial lesions in patients over the age of 18, and by the fact that these are much less common than DLGG overall , which is important given the known benefit of MSR for these patients , 11, 15.Given these limitations, we recommend against the use of large administrative databases to continue studying outcomes in DLGG management until there is greater specificity in the ICD coding system. Ideally, such studies should be conducted on prospectively collected databases designed specifically for DLGG, in which appropriate variables can be collected that are relevant to this patient population. Prospective health economic analyses, incorporating both procedural costs and concordant impact on quality of life, would help delineate the full benefit of MSR.We acknowledge that the goal of resection and biopsy are not the same. Biopsy is performed as a diagnostic procedure, often to guide future treatment decisions, whereas resection is an evidence-based therapeutic treatment. This study is not meant to question the utility of resection, and without outcomes data it would be impractical to do so. However, we felt that it would be impractical to present costs and complications without a comparison group. Biopsy was chosen as a comparator procedure since this was historically considered a viable alternative to resection. We hope that this information may serve as a basis for evaluating the cost-effectiveness of DLGG management in the future through prospective health economic analyses.In general, there is a scarcity of cost-effectiveness research in the neurosurgical literature . These avia prospectively collected databases designed specifically for DLGG, at least until improvements are made in general database variables and ICD coding.Few studies on DLGG management have evaluated national complications and costs, both of which impact a patient's quality of life post-operatively. To our knowledge, the present study is the first to employ the MarketScan research database in the DLGG population for this purpose. This data can be used in future health economic analyses to better understand the cost-effectiveness of DLGG interventions. However, our experience has also highlighted significant limitations in the utilization of administrative databases for the study of DLGG. Long-term outcomes should instead be assessed