Oxygen is vital in the treatment of illnesses in children and adults, yet is lacking in many low and middle-income countries health care settings. Oxygen concentrators (OCs) can increase access to oxygen, compared to conventional oxygen cylinders. We investigated the costs and critical success factors of OCs in three hospitals in Fiji, and extrapolated these to estimate the oxygen delivery cost to all Sub-Divisional hospitals (SDH) nationwide.Data sources included key personnel interviews, and data from SDH records, Ministry of Health and Medical Services, and a non-governmental organisation. We used Investment Logic Mapping (ILM) to define key issues. An economic case was developed to identify the investment option that optimised value while incorporating critical success factors identified through ILM. A fit-for-purpose analysis was conducted using cost analysis of four short-listed options. Sensitivity analyses were performed by altering variables to show the best or worst case scenario. All costs are presented in Fijian dollars.Critical success factors identifed included oxygen availability, safety, ease of use, feasibility, and affordability. Compared to the status quo of having only oxygen cylinders, an option of having a minimum number of concentrators with cylinder backup would cost $434,032  over 5 years which would be 55% (range: 41 to 64%) of the status quo cost.Introducing OCs into all SDHs in Fiji would reduce overall costs, while ensuring identified critical success factors are maintained. This study provides evidence for the benefits of OCs in this and similar settings.The online version contains supplementary material available at 10.1186/s12913-021-06687-8. Every year, over five million children die globally; a large proportion of these deaths occur in low and middle-income countries (LMICs), and most are preventable . PneumonOxygen cylinders have been the standard form of oxygen supply in most health facilities worldwide. They are expensive, heavy and difficult to transport, and require regular replenishment, all of which are barriers in LMICs . There i2) has the ultimate goal of achieving universal access to oxygen in Fiji. Oxygen concentrators were installed in three pilot sites  between March 2016 and August 2018. The costs and benefits of concentrator installation at SDHs in these sites were investigated to determine whether there is a case for further investment into an oxygen concentrator-based solution for oxygen delivery to SDHs in Fiji, and in similar settings.In Fiji, with a population of approximately 889,327  people sAn initial scoping visit to the three pilot sites was followed up by visits to each site to facilitate the collection of cost data. Data from the three sites were extrapolated to provide a cost estimate for expansion to the 16 remaining SDHs and the ongoing costs for all 19 SDHs over a 5-year period which is the approximate time estimated for concentrators to function before needing replacement.Multiple sources were used to collect data. The risks and benefits of cylinder versus oxygen concentrator use were documented through discussions with key clinical and administrative staff. The main discussion questions were related to ease of use, safety issues, training, costs, supply, and perceived benefits and difficulties, with discussions following along themes and issues raised by staff   exerciseRt / (1 + i)t was used for calculating the PV of monetary benefits. Rt was the savings in operating costs per year. The operating costs per year for each of the four options were calculated by dividing the operating costs by five. The savings in operating costs were then calculated by subtracting the yearly operating costs for each option from the Option One yearly operating costs. The discount rate per year (i) was 4% in New Zealand which was therefore used in the calculation [n) was 1 for the first year, 2 for the second, and so on. The PV was calculated for each year of the appraisal, which in this case is five. The sum of all five equations equals the total PV.All options were compared to Option One (status quo). Present value (PV) of monetary benefits is the current value of a future sum of cash flows, discounted at a ‘discount rate’. For this project, there were no incoming cash flows, so we used the savings compared to the existing operating costs. The formula of culation . The numPresent value of costs (PVC) is the capital costs spent at the start of the project. As Option One also has capital costs, the present value of costs is the difference between capital costs for Option One and the remaining three options (two to four), as these are extra costs over and above the existing system. Net present value (NPV) is the benefits minus the costs (NPV = PV (benefits) – PV (Costs)). NPV was calculated by subtracting the present value of monetary benefits from the present value of costs.Sensitivity analyses were performed by altering variables to show the best or worst case scenarios of the costs for the proposed expansion. The costs were altered from the preferred option for expansion. The estimated cost of the preferred option, and the best and worst-case costs, were compared to the costs for the existing oxygen system to determine if any of the changes to the variables made the preferred option no longer affordable.The SDHs and their dependent smaller facilities have oxygen supplies, however, they often need to ration oxygen in case of an emergency, and sometimes completely run out due to refill stations being far from the SDH and the time it takes to order and refill. This leads to delays or omissions in patients receiving oxygen.Oxygen cylinders are often large, heavy and difficult for staff to move within the facility and potentially hazardous when not attached to wall braces, as is often the case.Annually, the Fiji MoHMS spends approximately 2.5 million dollars on the supply of oxygen from one provider.Three key issues were identified from the investment logic mapping exercise:From the above three issues, critical success factors needed for the assessment of a preferred option of delivery of oxygen in Fiji must include availability, safety, ease of use, feasibility, and affordability.The preferred option is Option Three which is a combination of a minimum number of concentrators with a cylinder as back-up Table . The whoAfter undertaking sensitivity analyses, the whole of life cost for the preferred option ranged from $327,940 to $506,920 (Table Our results suggest that the installation of oxygen concentrators into sub-divisional hospitals in Fiji would be cost saving for the Fijian MoHMS. Moreover, it would help ensure that oxygen is continuously available, safer and easier to use, which is not currently the case. However, to realise these benefits, installation of concentrators would need to be optimised through professional installation, adequate staff training and good management and oversight by all related parties such as the Fiji MoHMS, clinical and biomedical engineering staff, and donor organisations.Studies undertaken in other LMICs have reported clinical and financial benefits of using oxygen concentrators , 22–25. While every effort was used to obtain reliable information for our analysis, the data have limitations. Data from the analysis of three pilot sites were used to calculate the costs of changes to the oxygen system in all SDHs therefore assumptions were required which may not be accurate for other sites. However, adjusting rates to show the best and worst case cost scenarios allowed for these variations and continued to show a cost benefit for the preferred option even with the worst case cost scenario. Oxygen use before the introduction of concentrators in the three sites is likely to have been rationed and to have increased after the introduction of concentrators. This is likely to make cylinder supplies appear less costly than if demand and supply parameters were applied identically. This adds additional reassurance that the findings in favour of concentrator-based supply solutions are robust. Our analysis was limited to SDHs and is therefore not indicative for the whole of the health services in Fiji. Neither is it indicative of costs in hospitals related to anaesthesia and intensive care, where high flows are used. Economies of scale and logistical considerations mean that supplying oxygen by concentrators in larger Divisional Hospitals or supplying facilities smaller than SDHs may vary to what is reported here. Oxygen demand within a country is difficult to estimate  particulInstalling and using oxygen concentrators in a country’s health system is not without its challenges. The warranty of the concentrators is for three of their expected 5-year lifespan, therefore the role of biomedical technicians is critical, as is having the relevant supply of spare parts, robust maintenance systems, and a back-up supply of cylinder oxygen. Changing staff behaviour to encourage them to use the concentrators is also a potential challenge, however, from discussion with staff in the sites we know that with good training staff prefered to use the concentrators. It is also worth considering where the funding for concentrators should come from, and in a study of the cost effectiveness of using oxygen concentrators in Papua New Guinea the authors reported them to be the “best-buy” for supply of oxygen that could be part of a national supply strategy rather than relying on donor support . To achiAn option not considered here is larger oxygen ‘plants’, which are based on the same principles as oxygen concentrators, used on a larger scale to supply piped oxygen systems in hospitals or to fill cylinders. The cost analyses for such plants appear favourable, but there are operational hurdles to their success in practice, particularly in LMICs . These iIntegrated national planning for oxygen supply and use, rather than ad hoc solutions at facility or health district level, is needed to optimise both availability for hypoxaemic patients and cost. Ensuring access to oxygen is likely to cost less per patient in large facilities than in small ones, but planning access nationally can prevent this becoming a diversion or barrier, by making the costs of universal access more transparent and able to be compared to the status quo.The current COVID-19 global pandemic has put the spotlight on emergency respiratory care, a fundamental component of which is access to medical oxygen. This analysis shows that in the Fijian context concentrator-based solutions are likely to provide security of supply that meets the needs of end users and suppliers. This is very likely to also be the case in other similar LMIC contexts, which are being disproportionately impacted by the current pandemic.Additional file 1. Topic guide for discussion with clinical and administrative staff.Additional file 2. Assumptions.Additional file 3. Acceptability of oxygen systems by health staff in sub-divisional hospitals in Fiji: Investment logic map.


At present, the doctor–patient relationships in Chinese medical and health institutions (MHI) are increasingly tense, and the reputation crisis challenges are being faced by MHI more frequently. However, the reputation crisis management level of the MHI is directly related to the future development and construction of the MHI and is an important management link that cannot be ignored. Therefore, how to quantify the impact of the relevant crisis on hospitals has become a major problem. First of all, this paper uses the situational crisis communication theory (SCCT) to combine the characteristics of hospital reputation crisis with the theory and classification of MHI reputation crisis from three perspectives: victim crisis, accidental crisis, and preventable crisis. Second, a more comprehensive analysis of MHI reputation crisis management model is conducted in the research cases, based on the relevant data of Union Hospital, Tongji Medical College Huazhong University of Science and Technology (UH), Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology (TJ), Zhongnan Hospital of Wuhan University (ZN), Renmin Hospital of Wuhan University (RM), and Maternal and Child Hospital of Hubei Province (MC). Third, we divide MHI reputation positioning into four types, namely robust, growth, fragile, and sensitive, and innovate SCCT to build a new MHI crisis classification type. Finally, this paper provides appropriate crisis management strategies for sample MHI based on the above examples and theories. Furthermore, we realize the lifecycle management of MHI reputation by identifying, evaluating and responding to reputation issues. This study provides a theoretical reference for the MHI reputation crisis management level and the adjustment of future management strategies. Medical and Health Institution (MHI) reputation is the rational cognition and emotional evaluation of the past and current behavior and results of a MHI through personal experience or through internet and word-of-mouth communication. For the 2019 China Hospital Rankings that were released by the Hospital Management Institute of Fudan University . Among tNowadays, there are mainly two perspectives on reputation research. One is from the perspective of economics, which regards reputation as an important mechanism to ensure the honest execution of contracts . The othMHI reputation refers to the reputation and reputation of the MHI in the public, which is an intangible asset and potential and important resource. MHI reputation management is the development and utilization of such intangible resources . The MHIThe existing research on MHI reputation is mainly reflected in the discussion of MHI reputation definition and reputation management. Asenjo et al.  proposedThe SCCT was proposed by Coombs . To quanAfter the crisis occurs, the organization's primary task is to prevent stakeholders from harming. Therefore, organizations must provide indicative information after a crisis to prevent people from being physically harmed and provide adaptive information to deal with people's psychological threats. Based on this, the organization can adopt the four basic crisis communication strategies: denial, downplay, reconstruction, and support. The key to matching crisis scenarios and crisis response strategies lies in their respective strengths and weaknesses. On the one hand, the attribution of responsibility becomes stronger from the victim type, accident type, and preventable crisis type. On the other hand, the tough attitude of denial, downplay, and reconstruction strategy weakens in turn. In this way, the two form a dynamic adaptation system.MHI reputation crisis management can refer to the classification of crisis in SCCT, list the common crisis scenarios according to the actual situation of MHI reputation, and adopt targeted crisis response strategies. That is, SCCT believes that organizations first classify the crisis when a crisis occurs and choose the most appropriate crisis response strategy after evaluating the variables that may affect the enterprise reputation. That is to say, different crisis communication strategies have different effects. The key to achieve the best communication effect is in the adaptation of communication strategies and crisis scenarios and to choose the corresponding strategies according to the size of responsibility of the organization. Specifically, when the organization (MHI) is a unresponsible victim crisis scenario, denial strategy can be adopted; when the organization (MHI) is a moderately responsible accidental crisis situation, excuse, rationalization, and other elimination strategies can be adopted; when the organization (MHI) is a highly responsible misbehavior crisis situation, the organization should not escape, should actively assume responsibility, and should adopt communication strategies such as correction and apology.According to the data analysis of this article, there are no major crisis events occurred in the five MHI in Hubei Province, mainly some smaller public opinion events. Therefore, the corresponding treatment of the response strategy will be unsuitable and needs to be adjusted accordingly. Then the strategy has been adjusted and corrected accordingly, and low victim crisis risk can be applicable to resistant management response strategy. High crisis risk can be prevented, and a gentle defensive strategy should be used.The traditional reputation index is generally used to measure the overall reputation level of the target entity over a period of time, and its performance characteristics are relatively single. As a subject that is constantly developing and changing, a MHI reputation level will be affected by various crises inside and outside of the hospital. To expand the scope of research and show the MHI reputation crisis management level more three-dimensionally, this article starts from the two dimensions of “one static and one move” and combines the static reputation index with the dynamic crisis management level to comprehensively describe the MHI reputation management situation in a three-dimensional manner, as shown in The MHI reputation crisis management index is composed of the MHI reputation index and the crisis response index. For the MHI reputation index, this paper evaluates the index through the comprehensive strength of the MHI itself and the evaluation of the MHI by the outsiders, namely the breadth of reputation (BR), strength of reputation (SR), and the degree of reputation (DR). On the other hand, for the crisis response index, this paper comprehensively considers the MHI's response efficiency and effectiveness when a reputation crisis occurs.Baidu index to reflect the influence scope of the MHI itself. The DR is based on the three subjects of MHI, netizens, and patients and comprehensively describes the MHI evaluation level from an objective perspective based on the ratio of positive and negative reports of the MHI, the ratio of positive and negative evaluations of netizens, and the satisfaction of patients. In addition, the crisis response index of the MHI includes crisis response efficiency and crisis response effect. The crisis response efficiency mainly depends on the MHI's handling methods and processing time. It is also a more conventional crisis response evaluation index.In the index model, the three dimensions of the MHI reputation index, namely the BR, SR, and DR, respectively, represent the popularity of the MHI, the strength of the MHI itself, and the evaluation obtained by the MHI, which can more comprehensively depict the reputation level. The SR takes into account the MHI technical equipment, scientific research level, and specialist strength and reflects the MHI own strength from the perspectives of hardware and software. The BR is constructed using the search index and information index in the In this paper, the UH, TJ, ZN, RM, and MC were selected as the research objects. On the one hand, the research of the MHI reputation evaluation and management level needs to obtain the hardware and software of the MHI before and after the crisis, and the general MHI do not have perfect relevant information, that is, the lack of scientific processing or analysis, so its reference is limited. On the other hand, UH, TJ, ZN, RM, and MC are all well-known MHI in Hubei Province and even the whole country, with great actual influence, more representative and more research value.Baidu Index from January 2020 to July 2021, and all kinds of emotional tendency data about the Internet platform are provided by the Qingbo Public Opinion System. In addition, before counting the data needed for the crisis response index, this article searched the crisis events of each MHI finally chose major events such as medical disturbance and medical accidents, and recorded the malignant degree of the crisis event and the MHI response, so as to complete the construction of the crisis response index. After obtaining data for all three indicators, the text is normalized, delegated and processed, and finally obtained from the bottom to top, as shown in Based on the above analysis, this paper collected and processed the data according to the construction model of MHI reputation crisis management index evaluated the specific crisis event indicators in each MHI, and finally calculated combined with these data. Among them, the data on the MHI technical equipment, scientific research level, and specialist strength are all from the relevant official websites, knowledge websites, major forums, and other public platforms. The search index and information index came from the It can be seen from The above MHI reputation crisis management model divides the index into reputation index and crisis response index. This paper considers two indicators comprehensively, starting from the reputation level of the MHI itself and crisis response ability, so as to dynamically describe the overall reputation of the MHI. Therefore, this paper uses the MHI crisis response index as the horizontal axis and reputation index as the vertical axis to establish a coordinate chart as shown in It can be seen from Based on the above analysis, it can be seen that after conducting reputation crisis management assessment, MHI managers need to clarify their own positioning, take different measures for different positionings, and achieve “grasp both hands and hard hands” in the reputation index and crisis response index, so as to effectively respond to external crises while improving their own reputation.Situational crisis communication theory defines the crisis from the subjective perspective of the audience and judges, the responsibility of the event according to the attribution theory in psychology . Coombs The 10 types of three clusters of Coombs are most widely used in crisis research. Therefore, on this basis, this paper further divides the MHI reputation crisis according to the attributes of the MHI and the needs of reputation management. According to the SCCT and the degree of MHI reputation crisis, the top 10 MHI reputation crisis types under the three crisis groups are obtained as shown in According to the previous literature review and empirical analysis of the model, it can be found that due to the halo effect, MHI with different reputation bases are greatly affected when a crisis occurs. MHI with a high reputation crisis management index have a strong reputation foundation and crisis response ability and often are more vulnerable to public trust, and the threat to the MHI reputation under the same crisis type is low, so response strategies cannot be selected based on the type of crisis. Based on the three-cluster crisis response strategy of Coombs and the reputation crisis management foundation of MHI, the following crisis management response strategy is obtained in (1) For “robust” MHI with a strong reputation basis and crisis management, defensive management response strategies can be applied, such as handling rumors and malicious medical disturbances. through legal channels, and adopting open and tough measures for unexpected or preventable crises. Due to its good reputation, the public is more inclined to stand on the MHI's position and hold a trust attitude when facing negative information from MHI. At the same time, because of its rich experience in crisis management, MHI have the ability to control the negative impact of crisis events when adopting defensive response strategies.(2) The location of the MHI reputation is close to the lower left area, indicating that the MHI reputation foundation and crisis management capabilities are weak and belong to “vulnerabilities.” Once a crisis occurs, it will have a greater impact on reputation. Therefore, a gentle defensive strategy should be used for crisis management to prevent negative information from spreading again, which exceeds the MHI's ability to respond to a reputation crisis.(3) For “sensitive” MHI with low reputation index but high crisis response index, the “reconstruction” response strategy is applied; that is, private mediation plans such as compensation and apology are adopted when a crisis occurs, to avoid the spread of negative information, and once again attack the weak reputation foundation. At the same time, “sensitive” MHI should pay more attention to basic reputation management, enhance their reputation breadth, strength, and reputation, and rebuild public trust.(4) For “growth” MHI with a high reputation index but a low crisis response index, adaptive management strategies should be used, and an appropriate crisis management plan should be selected according to the type of crisis and the degree of responsibility. “Growth” MHI have reputation-based advantages, but due to the lack of corresponding crisis management experience, directly adopting defensive response strategies may further create other reputational risks. Therefore, “growth” MHI gradually improve their reputation management capabilities in debugging response strategies and transform to a “robust” positioning.In summary, from the SCCT perspective, the adapted response strategy refers to a crisis response strategy that matches the type of crisis. It can be obtained from the strategy distribution map that the victim's crisis risk is low, which can be applied to the countermeasure management strategy; the preventable crisis risk is high, and a gentle defensive strategy should be used.In a case study of five MHI in Hubei Province, the reputation management strategy in Table obtained according to the one shown in 1. TJ and UH are suitable for the strategy of “resist” reputation management.TJ and UH have obvious reputation management advantages among the five MHI as a whole, but they still need to improve their ability to respond to reputation crises. TJ and UH are robust types of MHI reputation positioning, and their BR and SR have absolute advantages. Therefore, in the face of negative public opinions such as “difficulty in registering” and “unreasonable fees,” they should adopt active and defensive management strategies, dealing with malicious and false information through legal channels, responding to patient complaints in a timely manner, opening official accounts in major medical-related forums, paying attention to negative information, and actively interacting with netizens. In the process of reputation crisis management, TJ and UN can pay more attention to the prevention of socially sensitive events and deal with them in advance through crisis management cases in other MHI.2. RM is suitable for the strategy of “adopt” reputation management.RM is positioned as a growth-oriented reputation. It has certain reputation-based advantages but weak crisis response capabilities. It is suitable for adaptive management strategies; that is, when a reputation crisis occurs, first evaluate the risk status and learn from other MHI solutions to build reputation to manage the case database and gradually explore the reputation crisis management plan that suits the positioning and style of the MHI. RM should strengthen the monitoring of reputation crisis events and try to intervene in advance when the crisis expands.3. MC is suitable for the strategy of “defend” reputation management.MC is inferior to other MHI in terms of its own strength, such as BR and SR, and it has insufficient experience in handling reputation crises. It is in a fragile reputation position, so it is suitable for a moderate defense management strategy; first, pay attention to the internal management of MHI, strengthen the standardization of MHI staff training and product use, and minimize the probability of preventable crises; second, more public welfare activities can be carried out in the community and the Internet to gradually increase BR and DR.4. ZN is suitable for the strategy of “rebuild” reputation management.ZN has a low reputation index and is in a sensitive reputation position. It needs to rebuild its management strategy for reputation restoration. ZN has the strongest crisis management capabilities among the five MHI, but has the lowest DR. Therefore, on the one hand, it should maintain a high degree of sensitivity to negative information on the Internet and respond in a timely manner; on the other hand, it should rectify the content of patient complaints; in the event of an incident, try to choose a private mediation method to avoid secondary negative information due to the weak reputation at this stage.This paper constructs a MHI reputation crisis management index model and divides the index into two indexes, namely, a static MHI reputation index and a relatively dynamic crisis response index. The data of the five MHI UH, TJ, ZN, RM, and MC are used to compare the two indexes. These indicators were further subdivided and quantified, and finally the reputation crisis management index of these five MHI was evaluated and analyzed. The analysis results show that different MHI have their own characteristics in the two dimensions of reputation index and crisis response index. This article divides them into four types. Among them, TJ and UH are classified as “robust type” because of the high two indexes. The crisis response index of RM is low and is classified as “growth type.” The two indicators of the MC are low and are classified as “fragile type.” ZN has a low reputation index and is classified as “sensitive type.”Second, according to the three-cluster ten-type crisis research of Coombs, this paper classifies the MHI reputation crisis according to SCCT and the degree of MHI reputation crisis and redefines the ten types of MHI reputation crisis from the three degrees of victim crisis, accidental crisis, and preventable crisis.Finally, based on the above theories, this paper analyzes the targeted crisis response strategies of five sample MHI. Among them, the “robust type” MHI, namely TJ and UH, are suitable for the countermeasures of defensive management. “Fragile type” MHI, namely the MC, are suitable for mild defense strategies. “Sensitive type” MHI, namely ZN, should adopt a “rebuild” strategy, that is, promptly communicate compensation and apologies after a crisis event to avoid further expansion of the spread of negative information. “Growth type” MHI, namely the RM, should choose appropriate response strategies based on the degree of crisis and the degree of responsibility and require more flexibility.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.YL: writing—original draft preparation and conceptualization. XL: designing the framework and data collection. RD: methodology. TH: software. X-jW: writing—reviewing and editing. All authors contributed to the article and approved the submitted version.This work was supported by the Philosophy and Social Science research Project in Department of Education of Hubei Province (Grant no. 21G001), the National Social Science Fund of China (Grant no. 20&ZD058), and the Construction of Science and Technology Planning Project of Hubei Province in 2020 (Grant no. 2020041).XL was employed by company Hubei Media Group, Wuhan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Viral hepatitis remains one of the most significant health issues globally, directly responsible for over 1 million deaths each year and affecting almost 300 million people around the world. Scientific research in recent decades has brought about improvements in the lives of people living with chronic viral hepatitis. On the 29 July 2021, the Australian Centre for Hepatitis Virology (ACHV) for the first time held a public educational forum for the general public. The main aim of this event was to inform the affected community about the importance of scientific research and give an overview of upcoming developments in the field. Here, we provide a detailed report of the panel discussion  and provide strategies that can be used by other scientific societies to hold similar events in their own communities. Although current therapies can suppress hepatitis B virus (HBV) replication and reduce the risk of adverse outcomes, a finite-term therapeutic cure is still unavailable;There is no vaccine that protects against hepatitis C virus (HCV) infection or reinfection;The lack of rapid and available diagnostic tests for both infections remains a key obstacle to linkage to care;Access to information, treatment and care for people living with viral hepatitis is limited in many parts of the world;Stigma and discrimination against people with viral hepatitis limit their willingness to access health care and prejudices policies for community engagement, diagnosis, management, treatment and research funding.Ground-breaking scientific advances in hepatitis virology have been realised in recent decades. These have provided life-changing improvements for millions of people affected by viral hepatitis, particularly hepatitis B and hepatitis C . Despite the outstanding pace of progress in the field, important problems still remain:These issues contribute to the ongoing new transmission events that occur every year, adding to the number of affected individuals. At the same time, these issues also define the leading edge of medical research, which may not be well publicised to the lay community. We aimed to communicate this scientific focus and progress to the general public  in an interactive panel discussion with experts in the field.Here, we describe our event and provide potential strategies for others to convey the benefit of medical research, to successfully engage with affected communities and to improve researchers’ confidence in establishing their own outreach events.An interactive discussion panel discussion was organised by the Australian Centre for Hepatitis Virology (ACHV), the key national society for hepatitis virology research in Australia. The event aimed to provide (1) a background on the history of scientific research in viral hepatitis and how it has improved the lives of those affected by viral hepatitis and (2) an opportunity for those from the affected community to have their questions answered by leaders in the field.The panel as a whole had a broader experience to call on to answer questions posed by the audience;Given their non-overlapping expertise, the panel could ask each other questions to initiate constructive and informative conversations if the audience was not forthcoming with questions of their own;The audience would see the diversity of input required for scientific advances and their translation from “bench to bedside”.We invited experts from a broad range of backgrounds  to be hosts and panel members . This raThe panel discussion event was fully virtual and freely accessible to anyone with an Internet connection globally. This allowed the greatest number of people to join and interact, particularly with extensive restrictions on travel and gatherings due to the COVID-19 pandemic. The event was held at 6 p.m. AEST (UTC + 10), making the time zone amenable to live attendance for people across most of the world’s regions.https://www.eventbrite.com.au/ ) page was set up for free registration, which enabled us to monitor enrolments in real time and send group emails to all participants .Several platforms were employed to enhance participant experience and facilitate pre-event organisation. An Eventbrite ), an independent online platform for interactive discussions. On this platform, user-submitted questions can be up-voted by others, thus avoiding redundant questions. There were 11 questions posted on the Sli.do forum before the event . During the live streaming, the majority of people asked questions via the Zoom chat function.Registrants could ask questions either identifying themselves on the call or anonymously via Sli.do ) to centralise all national events focused on viral hepatitis taking place during the month.The poster was used to widely promote the event through professional networks, online patient forums, and social media. In addition to the ACHV membership base, we advertised the event through the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine eNewsletter. In addition, we took advantage of World Hepatitis Day on 28 July 2021, the day before our event. We registered our panel discussion on the website developed by Hepatitis Australia (The event was advertised on online platforms dedicated to the affected community chiefly by Dr. Thomas Tu (ACHV president) who openly lives with hepatitis B, adding trustworthiness and weight to the endorsement of the event. We targeted various social media platforms to gain broad awareness: Facebook, particularly groups visited by people with viral hepatitis ; Twitter, generating 1680 impressions; and LinkedIn, generating 828 views.A steady increase in registrant numbers was observed after registration was opened about 2 weeks prior to the event. By the time of the event, 69 participants had registered (excluding the panel). The Eventbrite page had been viewed 579 times (12% of those viewing had registered), indicating a good conversion rate to registrations. Most of the traffic to the event page was directed through a link , indicating that promotion through links shared by us to professional and patient networks had a larger impact compared to people finding the event on the upcoming events on Eventbrite. The resultant audience was a mix of scientists, students, health professionals and general public .https://youtu.be/rVEnz4PtrEY (accessed and created on 30 July 2021)). The link was sent to each registrant via email regardless of whether they were able to join live to maximise impact and as an advertisement for future events.The event was streamed on Zoom hosted by the University of Sydney on 29 July 2021. The entire event was recorded (informing participants prior to the event) and uploaded to YouTube , providing the background context of the medical progress in the last few decades. During this early period, hepatitis B could only be treated with symptomatic management and supportive care. If the disease progressed to liver failure and was treated with liver transplantation, reinfection and loss of the graft was common, occurring in 80–100% and 50%, respectively [Prof. Scott Bowden (an HBV researcher during this time) reflected that this paucity of treatment options provided scientists with great impetus to improve patient lives. As fundamental Hepatitis B and C research was (and still remains) underfunded, the field instead turned to repurposing other antivirals . In Australia, the establishment of the duck model of HBV served as a testbed for activity against HBV replication ,3,4,5. CHepatitis C virus  had not even been discovered yet at this time. Prof. Heidi Drummer provided an in-depth recount of the Nobel Prize-winning work  of HarveAfter these keystone studies, thousands of scientists had worked on developing systems to grow HCV in the lab and develop drugs against it. In particular, the group of Ralf Bartenschlager developed a replicon system  that allA large part of this progress has been due to earlier fundamental virology research, particularly the discovery of reverse transcription in retroviruses. Enzymes taken from these viruses enabled the initial identification of HCV and the cloning of its genome. Reverse transcription is also the sole target of all clinically used, direct-acting anti-HBV therapies. While not curative, these therapies can nevertheless suppress the virus and (as mentioned in the section above) have led to a dramatic increase in HBV patient survival.Current research in the HBV field is now focused on curative therapies. Given the establishment of robust assays and model systems, new treatments are now being developed specifically for HBV, rather than repurposing drugs from other viral infections. The panel was hopeful that some of the investigational therapeutics will likely be curative in at least a subset of people.Jennifer MacLachlan, Head of the Australian National Hepatitis Mapping Project, then reflected on the community-wide and global trends associated with these medical discoveries. After the advent of curative HCV treatments and their funding through the Australian national health care system in 2016, epidemiological trends have shown a dramatic decrease in the number of people living with, newly acquiring and dying due to HCV infections ,13. ThesAs previously mentioned, reduced mortality has been observed since the introduction of highly effective treatments for HBV in Australia . HoweverIn summary, these trends emphasise the need to keep up momentum in the delivery of HCV treatment and expand engagement in HBV care and access to diagnosis for both conditions. It also highlights the importance of progress in the development of a protective vaccine for HCV infection and an effective HBV cure.The majority of the audience was highly engaged and keen to take the opportunity to query the expert panel. Participants were eager to provide personal perspectives and experiences and showed interest in asking queries about their own health experiences . For this reason, we strongly recommend including an experienced clinician in the sub-speciality on the panel  to address these health-related questions.Some queries and comments were raised about the inequitable accessibility of clinical treatment. Audience members from low- to middle-income countries raised how it is difficult to access specialist care in their country, the prohibitive costs of treatment and the fear of stigma preventing any access to support. These issues caught our Australia-based, academic-centric panel unprepared, given the lower barriers to health care in their own experienced. While it was helpful to have a person living with chronic hepatitis B to empathise with the audience’s situation, it also could have been an opportunity for an international health policy or public health expert to provide a hopeful and insightful response. ACHV is considering inviting people with this expertise for future panels.In the end, a large influx of questions from the affected community was submitted both live and in the days leading up to the event. We had evenly split time between the background discussion and the Q&A session with the audience but in hindsight realise that the latter was much more engaging and in demand. In future events, we would likely alter the proportion of the event dedicated to audience participation .While this event was successful on the whole, we learnt several lessons to implement in future discussion panel events.Given the discussion, the panel felt that the approach in describing the history of scientific breakthroughs in both HBV and HCV was likely too broad and had too many important points over too many areas to be clearly understood or recalled by the non-specialist public. Provided resources are available, ACHV now intends to organise quarterly events and provide a more in-depth discussion on more specific topics.Given the academic and biomedical background of the organising committee, the description of the event on the EventBrite page had highlighted the importance of viral hepatitis and its impacts on mortality and morbidity. After a Facebook conversation about the EventBrite page , it becaWhile we had known to some extent that the fear of disease progression and death plays a significant role in the impacts of viral hepatitis , we had During the discussion, panel members were reminded that much of the cutting-edge scientific progress is far removed from the experiences of the people living with viral hepatitis. Outside of Australia and the rarefied environment of academia/tertiary clinics, many people still struggle to access basic health care, diagnostic tests and antiviral treatment.In future events, we will consider adding a section for the panel to discuss what they have learnt during the discussion. We believe that it would be empowering for the community to know that they are influencing and informing experts (as well as the other way around).Overall, the expert panel discussion was a successful event by several measures. We increased the awareness of both our society and partner groups, including HepBCommunity.org, a publicly available online forum specifically designed to link people with hepatitis B with each other and experts in the field (founded and directed by Dr. Thomas Tu). This site provides a gateway to ongoing engagement and education in viral hepatitis including that which we provided on the night. This effective outreach to affected communities is key to ongoing public health measures and public support for scientific research. Our experience also showed that, provided the opportunity, many from the affected community are willing to engage and that some had even planned on starting community-based organisations themselves.We would encourage other societies around the world to conduct similar events to broaden the access to informed experts in different countries, languages and disease conditions. Our event was limited by being held in English  and had limited expertise on the conditions outside of Australia. However, there is clearly demand for educational content such as this in the community.Communities that are more engaged with medical scientists are more likely to understand how public health decisions are being made. We feel that this is particularly important during this volatile period of increasing anti-expert and anti-science rhetoric. We believe that with these increased dialogues and respectful partnerships, researchers can play a more active role in society and its improvement.


As obligate intracellular parasites, viruses are intimately interconnected with their host cells. Virus–host cell interactions allow viruses to exploit cells for their own purposes, but they also provide a means for the host cell to combat virus infection. This close connection between host and viral processes means that the scientific fields of cell biology and virology have often inspired each other.In particular, many discoveries in cell biology have been made possible by the study of viruses, while, at the same time, our fundamental understanding of the virus life cycle is inherently rooted in the principles of cell biology. By examining cellular responses to infection, we can gain insights regarding the mechanisms associated with the restriction of virus infection or, in cases where control is ineffective, pathogenesis. Such knowledge is a prerequisite for the successful modulation of these responses to develop host-directed therapies for the control of viral infections. Furthermore, from a practical point of view, virus–host cell interactions also provide important targets for the development of indirectly acting antivirals, which have a reduced likelihood to develop resistance due to their reliance on host cell components.Cells compiles both review papers discussing the current state of our knowledge regarding important emerging themes related to virus–host cell interactions, and research articles reporting new discoveries in this scientific area. These publications cover various aspects of the virus life cycle, from virus entry, uncoating, and virus replication in specialized replication compartments, all the way to virus particle production. They also touch on the complex interplay of viruses with the immune system, and current topics such as the modification of viral RNAs.This Special Issue of One of the first interactions of a virus with its host cell is during the entry process, which is generally facilitated by the interaction of a virus surface protein with a cellular receptor, and sometimes by additional interactions with cellular attachment factors, in order to facilitate virus uptake. Here, a mechanism that is increasingly recognized as being exploited by diverse virus families is apoptotic mimicry, which in its canonical form involves the exposure of phosphatidylserine in the outer leaflet of the viral membrane. This exposed phosphatidylserine can then be recognized by host cell proteins, such as those of the T-cell immunoglobulin and mucin domain (TIM) family. Kirui et al.  demonstrIn a second study on virus entry, but from the perspective of the role that virus entry receptor expression can play in directing infection outcome in different tissues, DeBuysscher et al.  show thaAfter entry, the next hurdle that many viruses have to overcome in order to establish a successful infection is the uncoating of the virus genetic material to facilitate its release. In a featured review on Influenza virus uncoating, Moreira at al.  discuss For viruses that replicate in the cytoplasm, genome replication and viral transcription are increasingly being appreciated to take place in specialized replication organelles. For positive-strand RNA viruses, these are predominantly membranous structures. In contrast, for a growing number of negative-strand RNA viruses, viral RNA synthesis has been shown to be localized in inclusion bodies that are not delineated from their surroundings by membranes. Two reviews highlight the progress that is being made in understanding both of these types of replication organelles. Nguyen-Dingh and Herker  focus onWithin these replication organelles, transcription leads to the generation of viral mRNAs. However, what has remained underappreciated in virology is that, in many cases, these mRNAs can be modified by the addition of methyl groups by host cell proteins. In the second featured review of this Special Issue, Courtney  providesFinally, in order to complete their life cycle, viruses have to exit their host cell, and this process is often intimately interlinked with the subversion of cellular host factors. In the case of non-segmented negative-sense RNA viruses, particle production is frequently driven by a dedicated viral matrix protein. Focusing on the Ebola virus matrix protein VP40, Paparisto et al. show that the process of particle production is inhibited by the cellular protein HECT and RCC1-like containing domain 5 (HERC5) . HoweverOf course, host–pathogen interactions involved in antiviral control not only occur at the level of specific antiviral cellular factors or cellular antiviral responses, but can also include a broader range of interactions with the immune system. This is highlighted in a comprehensive review by Muralidharan and Reid, in which they illuminate the complex roles of neutrophils during arbovirus infections . Using eStaphylococcus aureus on the expression of bacterial virulence factors as well as on the infected host, particularly regarding its cytokine response and the integrity of the alveolar-capillary barrier. This work provides mechanistic support for the clinical observation that severe influenza infections are frequently complicated by bacterial coinfections.An equally complex but currently underappreciated topic is that of pathogen–host interactions in the context of coinfections involving several disease agents, and particularly co-infections of viruses and bacteria. In this context, a study by Nickol et al.  demonstrOverall, this Special Issue provides examples of the crucial role that virus–host cell interactions play in the biology of a diverse range of viruses, and highlights the importance of better understanding such interactions in order to be better able to combat virus infections and the mechanisms that contribute to pathogenesis and disease.


Both age and comorbidity are established risk factors for death among those infected with COVID-19. Because they often co-exist, it is difficult to assess if age is a risk factor on its own.We used administrative register data of the total Swedish population from 01/2015 until 07/2020. We stratified the population aged 70+ into three groups according to level of care . Within these groups, we explored the level of excess mortality in 2020 by estimating expected mortality with Poisson regression and compared it to observed levels. We investigated if excess mortality has been of the same magnitude in the three groups, and if age constitutes a risk factor for death during the pandemic regardless of level of care.Individuals living in care homes experienced the highest excess mortality . Individuals with home care showed the second highest magnitude , while individuals in independent living experienced excess primarily at the highest ages . Although mortality rates increased, the age-pattern of mortality during the pandemic resembled the age-pattern observed in previous years.We found stepwise elevated excess mortality by level of care during the first wave of the COVID-19 pandemic in Sweden, suggesting that level of frailty or comorbidities plays a more important role than age for COVID-19 associated deaths. Part of our findings are likely attributable to differences in exposure to the virus between individuals receiving formal care and those living independently, and not only different case fatality between the groups. Although age is a strong predictor for mortality, the relative effect of age on mortality was no different during the pandemic than before. We believe this is an important contribution to the discussion of the pandemic, its consequences, and which groups need the most protection.This study was funded by the Swedish Research Council for Health, Working Life and Welfare (FORTE: grant 2016-07115). Old age and comorbidity are both known to increase the risk of dying from COVID-19. This has been observed in the general population and COVID-19 patients. It could, however, be hypothesized that old age has a less pronounced role in risk of death from COVID-19 in healthier subgroups of the population than among frail or ill individuals. Furthermore, the role of individuals’ living arrangement, whether in care homes or independent living, for death from COVID-19 is also of importance in the context of evaluating policies aimed at protecting vulnerable groups. There is a lack of studies exploring the role of health status, living arrangement, and age in the total population considering the size of each subgroup.To the best of our knowledge, this study is the first to estimate age-specific risk of death during the pandemic in population groups stratified by level of care, which, in this setting, is also a rough proxy for level of frailty and underlying health status. Age-specific excess mortality during the first wave of the COVID-19 pandemic in Sweden is presented by three levels of care in individuals aged 70 years and older. Furthermore, this study shows the extent to which excess mortality levels have clearly differed between the three levels of care at a given age. Care homes have been at the center of attention in the discussions of how successful pandemic polices have been. It is clear from our results that the policy of protecting the old and vulnerable was not very successful during the first wave of the pandemic in Sweden.Age has a clear impact on the risk of death, and the risk of death increases with every passing chronological year. However, during the pandemic, the relative effect of age on mortality has not been different than before, as indicated by the almost parallel upward shift of death rates. Our findings suggest that level of care, and perhaps health status, play a more important role than age for COVID-19 associated deaths. Therefore, this suggests that health status should perhaps be given more attention when protecting vulnerable groups than age alone. Part of the findings are likely attributed to differences in exposure to the virus between individuals receiving formal care and those living independently.Alt-text: Unlabelled box1Old age, as well as poor health, have been identified as major risk factors for dying with COVID-19 . BecausA review and meta-analysis found a weak influence of age on COVID-19 disease severity when adjusting for important age-dependent risk factors Second, until recently, most studies have been based on COVID-19 cases only, and most often on patients with severe COVID-19 who were admitted to the hospital . WhiExcess mortality has been reported in many studies during the pandemic In Sweden, elderly care is dominated by the principle of “age-in-place”, meaning that old individuals continue to live at home for as long as possible The aim of the present study was two-fold. First, to examine if age-specific excess mortality during the first wave of the COVID-19 pandemic in Sweden, between January and July 2020, differed by level of care in individuals 70 years and older. Second, to assess how the increase in death risk with age differed across levels of care.22.1Our analyses were based on data from the Swedish Cause of Death Register Currently available information makes it difficult to assess with certainty who has died from COVID-19. For instance, COVID-19 deaths are inherently uncertain because their classification depends on intensity of testing, principles for assigning cause of death, and whether all or only hospitalized deaths are considered 2.2Monthly death counts and person years at risk for each month and care group by age and sex served as input for the estimation of the observed mortality rates in 2020. Person years were estimated by averaging the respective start-month and end-month population and multiplying it by the proportion of days in a given month among the total number of days in the respective year.2.3Expected mortality in 2020 for the three care groups is based on the mortality trend in the previous 5 years. We estimated expected mortality in 2020 using a Poisson GLM, which was the preferred choice in a comparison with a negative binomial GLM. We estimated separate models for each age group, care status group, and sex. Our model specification followed a Serfling-like regression model, which has frequently been used for the estimation of baseline mortality in seasonal settings 2.4Excess mortality was calculated by comparing the observed death counts and death rates in 2020 with the median and 95% prediction interval (PI) of the expected mortality in 2020 in the absence of COVID-19. We estimated both absolute levels of excess mortality, presented as death rates, and difference in death counts, and the relative mortality difference between the observed and expected mortality level within each care group and by sex and age.Finally, to compare the estimated excess of mortality with the COVID-19 death toll, we used numbers of COVID-19 deaths by age group and care status, published as publicly available statistics by the National Board of Health and Welfare in Sweden. We estimated to what extent COVID-deaths account for the total excess in mortality during the months April-June in 2020 stratified by age group.2.5The funding agency had no role in study design, data collection, data analysis, interpretation or writing of the report.3The proportion of the population, in men and women, respectively, who belong to each of the three groups at different ages can be found in Supplementary Fig. 1, the left panel showing the distribution during 2015–19 and the right panel, 2020. Before age 80, the proportion of individuals with public financed care, at own home or in care homes, did not exceed 5%. Compared to men, a higher proportion of women received care. In age group 85–89, around 25% of women received either home care or lived in a care home, while the corresponding proportion in men was around 20%. In age group 90+, more than 50% of the population received home care or lived in a care home. Even if subject to small variations, the distributions have been rather stable over the study period.However, even if the excess mortality was lower in a relative sense in the oldest age group in care homes, this group had the highest absolute number of excess deaths . In factThe relative excess mortality in the total population, during the whole period from April to June, in Sweden, was largest among women aged 75–79 years and men aged 85+, corresponding to around 40% higher than expected. COVID-19 related deaths accounted for most of the excess mortality; however, for women aged 75–79, there was a deviation. 3.1The results for the most affected region in Sweden, Stockholm, show the same overall pattern as for the rest of Sweden. However, excess mortality started earlier and was higher than in the rest of Sweden .4To the best of our knowledge, this is the first study that estimated and compared excess mortality during the COVID-19 pandemic in population groups stratified by level of care  and age. Most earlier studies have explored mortality differences by age and comorbidity based only on individuals infected by COVID-19. Based on these studies, it was unclear how the increase in mortality with age had been affected by the pandemic.Our results showed that before the pandemic began, observed mortality levels were similar to, or even at the lower end of, the predicted death rates for 2020 in Sweden. In March 2020, excess mortality was observed only in young-old women residing in care homes, whereas in April there was excess mortality in all three groups and at all ages. However, excess mortality was more pronounced among those receiving care than among the group in independent living. The relative increase in mortality with age was not larger during 2020 than what was expected from previous years. For the group living in care homes, we instead observed higher excess mortality among the younger ages than among the oldest old. Because excess mortality is estimated as the difference between observed and expected mortality, the magnitude depends on the predicted level of the expected mortality. We chose a regression approach to model our baseline because we compared three population groups with varying degrees of mortality improvement. However, in sensitivity analyses related to model specification and data input, where we tested the inclusion and exclusion of different months, the shape of the seasonal component, and the inclusion of 2020 summer months, we found the age pattern for mortality was consistent . That is, despite varying magnitudes of excess mortality, the finding that the relative effect of age on mortality seems to be similar during the pandemic as before the pandemic. This is not to be confused with the fact that age is indeed a strong predictor of death, and that the level of mortality was clearly highest at higher ages.Taken together, our results suggest that the comorbidity burden, measured by the level of care, plays an important role in the risk of COVID-19 associated death, regardless of age. This interpretation is supported by the gradient dose-response relationship between care and mortality, where care home residents experienced the greatest excess mortality, followed by those with home care, and finally those living independently. Furthermore, the results suggest that age alone is not necessarily a risk factor for COVID-19-specific death, beyond the “normal” risk of age that is present in absence of the pandemic. This interpretation is supported by the parallel shift in death rates over age observed in all three groups, rather than an exponential increase with age. This finding is in line with results of a recent US study It is likely that our findings also reflect the risk of exposure to the virus, in addition to the risk of dying from COVID-19. Although Individuals receiving care regularly meet home care providers, the group in independent living is likely to have fewer contacts outside their household. Even if the relatively healthy group in independent living may have been exposed to the virus during the early phase of the pandemic through social events and everyday living, they may have been able to avoid the virus to a higher extent by self-isolation. In Sweden, individuals 70 years and older were identified as a risk group and recommended to stay in isolation in late March 2020, something those with home care and in care homes could not do. Official statistics of confirmed COVID-19 in the groups with home care and in care homes in July 2020  indeed show that the proportion of confirmed COVID-19 cases was higher in care homes than in home care. This may indicate that individuals in care homes were more affected, and possibly also tested to a greater extent. The differences in positive tests vary greatly between age groups. For instance, in July 2020, for men, it differs between 0.5 to 11 percentage points depending on age, and among women between 0 and 27 percentage points. Because we also observed an age pattern of excess mortality in age groups with no difference in positive tests, we conclude that even if a different level of exposure to the virus is a likely explanation, it may not account for all of the difference in mortality.In line with previous studies, we found higher excess mortality among men than women during the pandemic, but the differences appear to be smaller when broken down by level of care. The finding that the sex ratio of COVID-19 mortality varies with age is consistent with past findings The considerably higher number of absolute excess deaths among women living in care homes is likely driven by the higher number of women living in care homes. We found higher excess mortality among males in independent living compared to women, possibly reflecting the fact that men of the same health status as women are less likely to receive home care because of support provided by their wives. In Sweden, it is more common for men than women to receive informal care The observed difference between all-cause mortality and COVID-19 deaths, primarily among women ages 75–79, can be explained by several factors. For instance, it may be that excess deaths are due to other causes besides COVID-19, that deaths were in reality caused by COVID-19 but individuals were not tested, or that the estimation of the expected deaths for 2020 based on previous years was too optimistic.It has been suggested that part of the excess mortality during the first wave of the pandemic reflects deaths occurring somewhat earlier than they otherwise would have among the frailest. If this were true, one would have expected a more pronounced reduction in mortality in the care home group compared to the group in independent living in July. We did not see this, at least not yet.The strengths of the present study include its population-based setting with data available on both deaths and the corresponding population at risk, reliable register information regarding living arrangement and deaths, and the possibility to use level of care as a proxy for health status. Additionally, our use of a regression approach to estimate baseline mortality to account for different levels of mortality improvement in the past, and therefore avoid expected mortality levels to be too pessimistic for groups with improvement and ensured that mortality was not underestimated.Some limitations of our study need mentioning. First, based on the available data it was not possible to identify the mechanism behind the relatively higher excess mortality in the two groups with care compared to the group in independent living. This could reflect a higher death risk due to poorer health status and a higher comorbidity burden, but differences in exposure to the virus depending on frequency of contact with health providers may also be at play. Also, a potential drawback of using excess deaths is that they mirror a net effect of both excess deaths and potentially saved lives during the pandemic. However, among individuals aged 70 and older, the pandemic is unlikely to have had any effect on saving lives, even if the seasonal flu was milder than most winters.5We found stepwise elevated excess mortality by level of care during the first wave of the COVID-19 pandemic in Sweden. We also found that mortality increased with age but that the relative effect of age on mortality is no different during the pandemic than otherwise. Of special note was the relatively higher excess mortality among groups receiving care, suggesting that health status plays a more important role than age for COVID-19 associated deaths. Part of our findings may be attributed to differences in exposure to the virus between individuals receiving formal care and those living independently.KM jointly conceived the study with ME, AA and ML. KM provided the data and ME analysed the data and created the figures. KM and ME have both verified the underlying data. KM and ME wrote the manuscript and AA and ML edited the manuscript. KM coordinated the project. All authors read and approved the final version of the manuscript.Aggregated data and codes for the estimation can be made available by the authors. Enquiries should be made to the corresponding author.Ethics committee approval was not required since the study was based on aggregated data.None of the authors have anything to disclose.


In light of the recent changes in the legal status of cannabis in Canada, the understanding of the potential impact of the use of cannabis by individuals suffering from depression is increasingly considered as being important. It is fundamental that we look into the existing literature to examine the influence of cannabis on psychiatric conditions, including mood disorders. In this article, we will explore the relationship that exists between depression and cannabis. We will examine the impact of cannabis on the onset and course of depression, and its treatment. We have undertaken a wide-ranging review of the literature in order to address these questions. The evidence from longitudinal studies suggest that there is a bidirectional relationship between cannabis use and depression, such that cannabis use increases the risk for depression and vice-versa. This risk is possibly higher in heavy users having initiated their consumption in early adolescence. Clinical evidence also suggests that cannabis use is associated with a worse prognosis in individuals with major depressive disorder. The link with suicide remains controversial. Moreover, there is insufficient data to determine the impact of cannabis use on cognition in individuals with major depression disorder. Preliminary evidence suggesting that the endogenous cannabinoid system is involved in the pathophysiology of depression. This will need to be confirmed in future positron emission tomography studies. Randomized controlled trials are needed to investigate the potential efficacy of motivational interviewing and/or cognitive behavioral therapy for the treatment of cannabis use disorder in individuals with major depressive major disorder. Finally, although there is preclinical evidence suggesting that cannabidiol has antidepressant properties, randomized controlled trials will need to properly investigate this possibility in humans. Depression is a leading cause of disability in the world , 2 with Cannabis is a widely used substance with pleotropic effects and has been proposed both as a treatment for and as a cause of depression. Cannabis is composed of 60–500 different compounds including a class of chemicals called cannabinoids –6; of thThe balance of harmful and therapeutic effects of CU in depression has not yet been clarified .This review aims to synthesize the literature pertaining to the relationship between depression and cannabis use (CU). Particular attention to the potential mechanisms involved in this association will be considered.Cannabis is one of the most used substances worldwide . After aCU is widespread among younger individuals with 7.6 million users in the 18–25 age group and 1.6 million in the 12–18 group in the US in 2017–2018 . A 2017 The definitions of substance use disorders differ across systems of diagnostic classification . DSM-IV The risk of developing dependence is about 9% and rises to 16% if CU is initiated in adolescence . PrelimiThe prevalence of CU has increased with a prevalence in the US of 4.1% between 2001–2002 and 2012–2013 and 9.5% respectively , 22.In the US, Colorado and Washington were the first states to make recreational use and sale of cannabis legal in the United States in 2014, although medical marijuana had already been legalized in Colorado since 2000 . FollowiThe frequent use of cannabis is associated with a plethora of negative health and social consequences , 22. WheThe endogenous cannabinoid (or endocannabinoids) system (ECS)  is involThe activity of the ECS is mediated by at least two cannabinoid receptors (CB1 and 2) and endogenous cannabinoids [2-arachidonoylglycerol (2AG) and anandamide] . THC is The ECS is further involved in the modulation of the hypothalamic pituitary axis (HPA) and brain derived neurotrophic factor (BDNF) , 33. TheIn vivo electrophysiological studies in rats have shown that acute or chronic low-dose stimulation by a full or partial agonist of the CB1 receptor produces an activation of the serotonin (5-HT) neurons in the dorsal raphe nucleus and increases their firing rate. On the other hand, sub-chronic or long-term high-dose stimulation by a CB1 receptor agonist causes an important decrease in the firing rates of the 5-HT cells of the dorsal raphe nucleus . Risk factors include female gender and earlier age of onset of use . The preWhile these results may be interpreted as indicating that cannabis “causes” depression, there are also data suggesting alternative interpretations, namely that the causal relationship may involve an increased likelihood of CU in individuals with depression. The high rates of lifetime CUD in the population of individuals with MDD (39%) is much higher than in the general population . Indeed,Evidence regarding the effect of cannabis on the age of onset of depression is inconsistent. A population based longitudinal study published in 2017 reported that the onset of depression occurred at a younger age in the non-cannabis using population than in those who used cannabis . HoweverOverall, studies support a bidirectional relationship between depression and CU. In other words, studies support the view that CU is a risk factor for developing depression , 58, 71.In the general population, cannabis use is associated with psychomotor retardation and emotional withdrawal , 30, parAnhedonia is a prominent symptom of depression and engages a broad network of neuronal circuits . CannabiIn individuals with MDD, CU and CUD are associated with having more symptoms than in individuals with MDD who do not use cannabis. These symptoms include anhedonia, changes in weight and sleep, as well as psychomotor changes , 64. AnoCU seems to have prognostic implications. Evidence from a population-based longitudinal study in individuals with baseline depressive disorder and varying levels of cannabis usage showed that there was a significant association between the level of CU and the persistence of depressive symptoms at follow-up. However, remission of MDD was not significantly different between those with CU, CUD, or no use . A largeResults from different studies are inconsistent with regards to the suicidal risk associated with cannabis in individuals with MDD. In one study, the OR associated with suicidal ideation in people from the general population using cannabis compared to non-users was 1.50 . A CanadCannabis withdrawal can occur amongst regular or heavy users at cessation. The reasons that motivate CU may vary . Using cAt the neurobiological level, CB1 receptor density in the frontolimbic system has been shown to be lower in people consuming cannabis regularly. Those alterations with daily CU are reversed following a month of abstinence , 95. ThiThe impacts of cannabis on cognition in the general population are more fully described in another article in this issue. By comparison, there is a dearth of knowledge regarding the effect of CU on cognition in depression. Cognitive complaints feature among the commonly reported side effects of CU . BrieflyCannabis use is also associated with residual impairment in cognitive performance in healthy individuals , 18, in Another factor to consider is that the effects of THC and CBD on cognition may be in opposite directions. However, this is as yet unproven . FurtherCognitive deficits are ubiquitous in MDD , 98. Of Knowledge is sparse regarding the interactions of the cognitive deficits of MDD and those linked to CU. The cognitive deficits linked to CU and MDD may be additive, especially those involving verbal learning . HoweverPreclinical studies show that antidepressant treatments , modulate the ECS , 63, 117The quality of evidence concerning the use of medical marijuana in the treatment of psychiatric disorders such as depression is low . To our Clinical trials using medical marijuana and its by-products for other psychiatric and medical conditions, which included depression as a secondary outcome, have generated intriguing signals. For instance, it was found that the oral administration of nabiximols   for numeThere has been little research into the treatment of CUD and comorbid MDD and the available data did not signal any efficacy for pharmacological treatment , 133. SeThere is no current scientific evidence that marijuana is in any way beneficial for the treatment of any psychiatric disorder. In contrast, current evidence supports, at minimum, a strong association of cannabis use with the onset of psychiatric disorders”  on treatment. Low doses of cannabis or its derivatives should be tested, as there is a clear signal that there is a different pharmacological effect of high and low dose. Future research should consider that this complex molecule also has the potential for drug-drug interactions –139. TheFor those who suffer from MDD and comorbid CUD, there is an urgent need to investigate, in well-designed trials, the potential efficacy of motivational interviewing and cognitive behavioral therapy. Such interventions have been shown to be efficacious for the treatment of CUD in individuals with no major psychiatric disorder. It remains to be determined if these interventions are also efficacious in individuals with MDD and CUD.This review was not systematic and did not restrict the definition of depression to a clinical diagnosis of MDD. Some articles used cut-off scores on scales to define depression. Further, the literature presents inconsistent results, which may be a consequence of the lack of precision regarding the concentrations of THC, CBD, and the strains consumed. Finally, some of the studies were small and thus, their results may not be generalizable.CU, in particular of cannabis products higher in THC content, is likely to be associated with increased adverse psychiatric effects, including depression. Indeed, meta-analyses on the subject seem to show that cannabis use may be a risk factor for the development of depression. However, a bidirectional relationship has also been described with depression being a risk factor for cannabis consumption as well as the reverse. Gender and youth may confer increased vulnerability to the adverse effects of cannabis.There is evidence that the endocannabinoid system is involved in the pathophysiology of depression. In the future, larger studies in the field will be needed to demonstrate this involvement, especially positron emission tomography studies examining different components of the endocannabinoid system. Components of this system are clearly potential targets for new therapeutic interventions for depression.Preliminary evidence from clinical trials shows that low doses of cannabis and its products have different and potentially beneficial effects, in contrast to higher doses which are associated with adverse effects. While some preliminary data indicates less deleterious and possibly positive effects of CBD in depression, it is premature to recommend CBD as a treatment for depression . RCTs onCL and ST were central to gathering data and writing the manuscript. AK and SP reviewed the manuscript. All authors contributed to the article and approved the submitted version.AK has consulted with Spectrum Therapeutics and Tilray in an advisory, mentorship and educational role. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Early palliative/supportive care (ePSC) is a medical intervention focused on patient’s needs, that integrates standard oncological treatment, shortly after a diagnosis of advanced/metastatic cancer. ePSC improves the appropriate management of cancer pain. Understanding the semantic and emotional impact of the words used by patients to describe their pain may further improve its assessment in the ePSC setting. Psycholinguistics assumes that the semantic and affective properties of words affect the ease by which they are processed and comprehended. Therefore, in this cross-sectional survey study we collected normative data about the semantic and affective properties of words associated to physical and social pain, in order to investigate how patients with cancer pain on ePSC process them compared to healthy, pain-free individuals. One hundred ninety patients and 124 matched controls rated the Familiarity, Valence, Arousal, Pain-relatedness, Intensity, and Unpleasantness of 94 words expressing physical and social pain. Descriptive and inferential statistics were performed on ratings in order to unveil patients’ semantic and affective representation of pain and compare it with those from controls. Possible effects of variables associated to the illness experience were also tested. Both groups perceived the words conveying social pain as more negative and pain-related than those expressing physical pain, confirming previous evidence of social pain described as worse than physical pain. Patients rated pain words as less negative, less pain-related, and conveying a lower intense and unpleasant pain than controls, suggesting either an adaptation to the pain experience or the role played by ePSC in improving patients’ ability to cope with it. This exploratory study suggests that a chronic pain experience as the one experienced by cancer patients on ePSC affects the semantic and affective representation of pain words. Early palliative/supportive care (ePSC) is a medical intervention integrated with standard oncological care, shortly after a patient is diagnosed with advanced/metastatic cancer. ePSC focuses on the patients’ needs and is meant to offer the best possible quality of life to cancer patients and their caregivers. Indeed, in the last years, several randomized controlled trials have shown that ePSC may lead to a better quality of life and decreased depression –6, lowerAccording to the World Health Organization, the beneficial effects of ePSC arise from an “early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual” . Pain iswww.vitaltalk.org) have been proposed )proposed .It is well established that suboptimal communication can negatively affect clinical outcomes ,21. The Undeniably physical pain represents only one of the two sides of the pain experience of oncological patients. The psychological and social suffering associated with this illness represents the other side .Macdonald & Leary  coined tSocial pain is commonly experienced and reported by cancer patients because of the impact of the diagnosis on their social life. This suggests that this component of the pain experience should not be ignored and that the assessment and management of patients’ physical and social pain should not be separated.Albeit words represent the main tool we use to describe physical and psychosocial pain, translating these experiences into words is difficult and often frustrating given the subjective complexity of pain. To overcome this problem in the clinical practice, several medical doctors proposed to administer pain questionnaires to assess the pain experienced by patients. For instance, the McGill Pain Questionnaire  is basedAn extensive psychological literature has shown that the emotional content of words, as well as many other word characteristics , affects the ease with which we comprehend words and sentences ,48. Howelancinante, piercing) or social pain .The main aim of this cross-sectional survey study was to unveil the semantic and affective representation of physical and social pain in a sample of patients with cancer pain on ePSC. To investigate wheteher and the extent to which their condition of chronic pain modulates this representation, we compared the data emerging from patients with those of healthy, pain-free, matched individuals. To this aim, we asked patients and controls to rate the semantic and affective characteristics of 94 Italian words conveying physical pain  were consecutively recruited from March 2018 to March 2019 at the Oncology and Palliative Care Unit, Carpi Civil Hospital, within the Local Health Unit in Modena. Since 2012, an interdisciplinary working group operates at the Oncology and Palliative Care Unit of the Carpi Civil Hospital. This group integrates primary oncologist specialists with an ePSC team in order to provide comprehensive symptom management and psychosocial, spiritual, and emotional support to cancer patients and their relatives, from the time of diagnosis of advanced/metastatic disease, onward. Specific guidelines ,57 ensurThe eligibility criteria for patients to be included in the study were to have an advanced/metastatic cancer diagnosis with severe cancer pain, willingness to participate, Italian as mother tongue , age ≥ 18 years old, no cognitive impairment , no history of psychiatric or neurological disorders, and no current use of psychoactive medications.The control group consisted of 124 healthy, pain-free participants  recruited in several community and senior centers in the Modena district from June 2018 to September 2019. The recruitment occurred through flyers distributed in local community and senior centers . The flyers reported the starting of a study on pain language in clinical and non-clinical settings based on questionnaires and indicated the presence of a researcher recruiting healthy volunteers to participate in the study. The eligibility criteria for controls to be included in the study were willingness to participate, absence of past or actual diagnosis of cancer and/or other chronic pain diseases and numerical rating scale equal to zero during the previous 24 hours, at the time of enrolment, no first-degree relatives with cancer, Italian as mother tongue , age ≥ 18 years old, no cognitive impairment , no history of psychiatric or neurological disorders, and no current use of psychoactive medications.The two overall groups were matched for gender, age, and educational level.Participants provided signed informed consent prior to data collection. The study was performed in accordance with the ethical standards of the 2013 Declaration of Helsinki and was approved by the Ethics Committee of Modena (N. 255/17).dolore (pain) as an anchor point and selected the content words co-occurring with it in a window of 25 words to the left and 25 words to the right of the word dolore in linguistic corpora, medical dictionaries, blogs, and pain questionnaires.A consensus group of five clinicians  with a long-term expertise in ePSC was asked to select the pain words most frequently used in doctor-patient communication based on the dataset of 512 physical and social pain words collected in our previous study . In theThe consensus group received an online survey with a brief description of the aim of the study and was asked to rate how frequent was the use of each word of the dataset in doctor-patient communication in oncology. The rating scale reported below each word went from Not frequent at all (1) to Extremely frequent (7). For each word, the mean, median, standard deviation, and internal consistency  of the ratings of the consensus group were calculated. Before starting the online survey, we established a maximum of 100 words to be included in the study to limit the cognitive load of the task. We selected the words with the highest median value and rating consistency. This led to a list of 94 words , of which 75 associated to physical pain and 19 to social pain  followed by an introduction explaining the aim of the study and the duration (approximately 20 minutes per questionnaire). Each word list was preceded by a definition of the variable to be rated and an explanation on how to use the Likert (or VAS) scale. In order to reduce the support of the interviewer and possible biasing effects, two examples of words rated with extreme values were provided  , with Age and Education as significant predictors ; Valence , with ESAS, SBI-15R Belief, and SBI-15R Support measures as significant predictors ; and Unpleasantness , with ESAS and ISH as significant predictors .This exploratory cross-sectional survey study revealed important differences in the semantic and affective representations of pain words in cancer patients on ePSC and healthy, pain-free, matched individuals. The study also highlighted important differences between physical and social pain words. Specifically, both groups perceived social pain words as significantly more negative and more associated to pain, replicating what was found in our previous study on healthy young participants . This reUnexpectedly, despite the fact that differently from healthy, pain-free controls, oncological patients experience severe pain, they rated both physical and social pain words as less negative than controls. One possibility is that this may reflect a long standing and suffered adaptation to illness and to the correlated pain experience. Another possibility, which should be further explored by specific studies, is that the ePSC treatment received by patients improved their ability to cope with the affective impact of illness leading to a perceived decreased negativity of pain words.Patients rated social pain words as more negative, more arousing, more pain related, and conveying a more intense and unpleasant pain than physical pain words. This may reflect the fact that ePSC is first devised to treat physical pain at a shorter lag via analgesic therapy . In contOncological patients considered the words associated to social pain as more arousing than those expressing physical pain. In contrast, healthy, pain-free participants considered physical pain words as more arousing than social pain words. This group difference may reflect the threatening connotation of cancer that inspired the ratings of physical pain words in controls. This threatening connotation is less relevant to oncological patients in ePSC, presumably because physical pain is pharmacologically controlled.Differently from controls, patients rated social pain words as more familiar than physical pain words. Admittedly, we do not have an explanation for this result. One possibility is that the higher familiarity of these words may reflect their higher relevance to patients. Another, not alternative, possibility is that it may reflect the relevance attributed by ePSC to the social aspects of cancer leading to a more extended use of these words during doctor-patient verbal exchanges.Notwithstanding the fact that physicians should avoid using medical jargon, large part of the literature on doctor-patient communication reports that, typically, doctors use a lexicon unfamiliar to patients, leading to a discrepancy between the words commonly used by doctors and the meaning actually understood by patients ,72. ThisThe lower the symptom burden, the less negative and unpleasant were pain words for the patients. In addition, the larger the availability of spiritual and religious resources, the less negative were perceived pain words. At the same time, the more the patients needed a community support, the more pain words were negative. This may reflect an important link between community support and illness coping. However, the vast literature about the effects of spiritual beliefs and community support on illness perception is far from presenting a homogenous picture . Some stper se. Future studies should be carried out to disentangle the effects of illness and cancer care treatment on the semantics of pain.Admittedly, this exploratory cross-sectional survey study has some important limitations. The first is associated to a possible sampling bias. Since healthy controls volunteered to participate in a study generically described as concerning the language used to convey pain experiences, only those having less fear of pain may have participated as it has been observed in experimental pain research . HoweverIn conclusion, to the best of our knowledge, this is the first study showing that a severe illness condition like advanced/metastatic cancer affects pain word representations. Indeed, the semantic and affective representation of the words expressing physical and social pain of oncological patients on ePSC differs from that of matched healthy, pain-free controls. This finding is supported by the studies showing how pain leads to alterations of physiological and psychological processes of pain perceptions and pain-related behaviors ,77. MoreInvestigating how oncological patients on ePSC perceive the lexicon of pain can be of help in improving the quality of doctor-patient communication and provide doctors with new tools for assessing how much word meaning and affect are shared with their patients. Since language mediates the ways in which individuals experience illness and has the potential to affect its course, suboptimal communication can negatively impact the patients’ clinical outcome . As SemiS1 Table(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.