Our model is validated through the experimental results. We also investigate various dosing strategies to improve treatment outcomes. Our study reveals that tumor killing rate by cytokines, cytokine decay rate, and tumor growth rate play important roles on both the OVT monotherapy and the combination therapy. Moreover, parameters related to CD8+ T cell killing have a large impact on treatment outcomes with OVT alone, whereas parameters associated with IFN-g strongly influence treatment responses for the combined therapy. We also found that virus killing by NK cells may halt the desired spread of OVs and enhance the probability of tumor escape during the treatment. Our study reveals that it is the activation of host anti-tumor immune system responses rather than its direct destruction of the tumor cells plays a major biological function of the combined therapy.Oncolytic ability to direct target and lyse tumor cells makes oncolytic virus therapy (OVT) a promising approach to treating cancer. Despite its therapeutic potential to stimulate anti-tumor immune responses, it also has immunosuppressive effects. The efficacy of OVTs as monotherapies can be enhanced by appropriate adjuvant therapy such as anti-CTLA-4. In this paper, we propose a mathematical model to explore the interactions of combined therapy of oncolytic viruses and a checkpoint inhibitor, anti-CTLA-4. The model incorporates both the susceptible and infected tumor populations, natural killer cell population, virus population, tumor-specific immune populations, virus-specific immune populations, tumor suppressive cytokine IFN-g, and the effect of immune checkpoint inhibitor CTLA-4. In particular, we distinguish the tumor-specific immune abilities of CD8 Oncolytic virotherapy has shown promising anti-tumoral effects in numerous basic and clinical research. Besides the oncolytic ability to direct target and lyse tumor cells, oncolytic viruses (OVs) also can be designed to selectively replicate to kill tumor cells while preventing their binding to and replication in healthy normal cells through engineered mutations . Neverth+ T cells requires two signals. The first signal occurs when a naive CD8+ T cell encounters and interacts with an antigen presenting cell such as a dendritic cell through the T cell receptor Infected rding to .Oncolytic virus. An infected tumor cell can produce many new viruses after being lysed. The burst size of virus particles released per lysed infected tumor celll, ows from . Viruses−1 as in . Virus krding to .+ T cells).Tumor-specific immune cells (CD8 Tumor cells activate CD8+ T cells with the rate ken from . Range oled from  with 10−ted from . The deaken from . T cells+ T cells).Anti-tumor immune cells (day+ T cell is estimated as + T cells compared with CD8+ T cells ,,5], tumoof cells . The sim+ T cells, CD4+ T cells, and NK cells. For simplicity, the initial settings of anti-tumor immune cells of CD8+ T and CD4+ T cells are assumed to be the same with We start our numerical investigation on the dynamics of the model given in Section 2.1.1 by showing that our model output is in reasonable agreement with the data given in Figure 2c of Engeland et al. . For pre104 from .Validation starts from the case of no treatment. Our simulation results show that the tumor grows up to n day 18 . For treIn the above experiment, none of the treatment protocol can suppress the tumor completely on day 18. We continue to investigate whether tumors can be completely killed (the number of tumor cells is less than one) on day 18 post implantation with the same treatment schedule but various dosages. We either vary the amount of oncolytic virus or the blockade rate of CTLA-4 or both. With the same initial settings and obstructing rate of CTLA-4,  used in  and 107 03–1010) . Thus, tu. When the CTLA-4 blocking rate is varied between Next, we examine the influences of the blocking rate of CTLA-4 to the tumor size on day 18 by fixing the amount of oncolytic virus at Following from the above results, the level of oncolytic virus and the rate of blockade of CTLA-4 have deterministic influences on the treatment outcomes. With the above suggested treatment protocols, either the therapeutic outcomes can be improved or the tumor can be eradicated on day 18 after implantation. Observe that the level of oncolytic virus or the CTLA-4 blocking rate has to be high to eradicate the tumor on day 18. The high level of dosages may result in immense immunopathology and cause immune-related adverse events. Therefore, we continue to explore the possible treatment protocol of effective therapy with reduced dosages. If We start by performing global sensitivity analysis of mono-therapy of OVT and also of combined treatment of OVT and anti-CTLA-4 to replicate in silico of a virtual experimental trial with 500 different mice. Sensitivity analysis is used to identify primary parameters that influence treatment efficacy. The majority of range of parameter values are estimated based on one over ten to twice the baseline values as in , and othrom zero .In this subsection, we investigate the model results when the immune checkpoint inhibitor is not applied. + T cells + T cells We now discuss the model results when combined OVT and the immune checkpoint inhibitor, anti-CTLA-4, are administered. + T cell killing play significant roles for OVT only therapy, whereas parameters related to the level of IFN-+ T cells are important for combined OVT with anti-CTLA4. In addition, the tumor growth rate, decay rate of tumor-suppressing cytokines, and tumor killing rate by cytokines are important factors influencing the behavior and fate of the tumor.Following from the above analysis, parameters + T cells. With anti-CTLA-4, the PRCC between + T cells gives more significance to the efficacy of the combined treatment than to the effectiveness of the sole OV therapy. The second and third marked distinction between current analysis and the result with sole OVT are related to the parameters + T cells, respectively. With anti-CTLA-4, the PRCC values of + T cells contributes more significantly to the cogency of the combined treatment than to the effectiveness of sole OVT. We also note that the tumor growth rate, To pinpoint the parameters that have a major effect on the combined therapy in relation to the sensitivity analysis of monotherapy of OVT, we investigate the rate of PRCCs between the analysis with sole OVT and the analysis of combined therapy. Among significant parameters, the most marked distinction between this part of analysis with the previous analysis of monotherapy of OVT is the parameter Particularly, we are interested in the role of oncolytic viruses on the treatment success. To study this effect, we implement different global sensitivity analysis by varying only those parameters associated with the OVs while keeping all other parameters fixed. This simulates an experiment of mice with comparable similar tumors and immune response but treated with various characters of viruses. We realized that the most two significant oncolytic virus-related parameters are the killing rate  rapidly . This ra rapidly ,51. This rapidly .The right panel in + T and CD4+ T cells. In our model, CD8+ T cells play a direct role of tumor killing, whereas CD4+ T cells kill cancer cells through cytokines they produced. T cells are also recruited by immune cells which become activated when they encounter the oncolytic viruses. Another group of immune cells we considered in the model is NK cells. They can be specific or non-specific during oncolytic virotherapy. NK cells become activated due to immunogenic cell death of infected tumor cells and interferons. They kill tumor cells and clear free viruses. Cytokines activated by both susceptible and infected tumor cells, and secreted by activated T cells and NK cells, conduct the indirect killing. CTLA-4 molecules are expressed on CD8+ T and CD4+ T cells and can prevent the cytokine production. Fragments from infected cancer cells activate the anti-viral immunity which subsequently kills infected cells and clear free virus. Our study focused on the transient behavior of the system because the tumor-immune dynamics are displayed only within few days/weeks after the initial injection of OVs in most of the pre-clinic studies as well as in the mouse experiment. Our model was supported by the experimental data of Engeland et al. [In this work, we developed a mathematical model to investigate the treatment of murine model of malignant melanoma B16-CD20 using an immune checkpoint inhibitor anti-CTLA-4 and OVT. The model is constructed to describe the interactions between the tumor populations (susceptible and infected), virus population, tumor-specific CTL response, natural killer cell populations, virus-specific immune populations, tumor suppression cytokines, and the effect of immune checkpoint inhibitor anti-CTLA-4. In particular, we considered the effects of both types of effector cells, namely CD8d et al. , which s+ T cells killings have a large impact on the treatment outcome with OVT alone, whereas parameters related to IFN-+ T cells strongly influence treatment responses for combined treatment with anti-CTLA-4. In addition, tumor growth rate, decay rate of tumor-suppressing cytokines, and tumor killing rate by cytokines are important factors in influencing the behavior and fate of the tumor treatment. We also observed that the most three substantial differences between analysis with combined OVT and anti-CTLA-4 and the analysis with monotherapy of OVT are the measure + T cells, the tumor killing rate + T cells. It suggests that the IFN-+ T cells associated with immunity takes part in a much more important role in responding to the auxiliary therapy than to the efficacy of sole OVT. In addition, we performed sensitivity analyses only for parameters directly related to the oncolytic virus. One of the significant OV related parameters is the killing rate We performed sensitivity analyses with OVT alone and also with the combined therapy of OVT and anti-CTLA-4 to determine parameters that are most significantly impacting the tumor response to treatments. Our study revealed that parameters related to CD8y system . Immunosy et al. . With coDespite the model’s ability on explaining how anti-CTLA-4 can improve virotherapy, we acknowledge that the model has some limitations. Our model is based on the population level interactions and does not account for subcellular events and stimulatory pathways. For example, the effect of IFN-pression , TLR-ligpression , and T cpression  are not


Whole genome sequencing of SARS-CoV-2 has occurred at an unprecedented scale, and can be exploited for characterising outbreak risks at the fine-scale needed to inform control strategies. One setting at continued risk of COVID-19 outbreaks are higher education institutions, associated with student movements at the start of term, close living conditions within residential halls, and high social contact rates. Here we analysed SARS-CoV-2 whole genome sequences in combination with epidemiological data to investigate a large cluster of student cases associated with University of Glasgow accommodation in autumn 2020, Scotland. We identified 519 student cases of SARS-CoV-2 infection associated with this large cluster through contact tracing data, with 30% sequencing coverage for further analysis. We estimated at least 11 independent introductions of SARS-CoV-2 into the student population, with four comprising the majority of detected cases and consistent with separate outbreaks. These four outbreaks were curtailed within a week following implementation of control measures. The impact of student infections on the local community was short-term despite an underlying increase in community infections. Our study highlights the need for context-specific information in the formation of public health policy for higher educational settings. However, lower population immunity among children, adolescents and younger adults2, the occurrence of infection despite vaccination3, and the emergence of vaccine escape variants5 threaten the long-term ability of the national vaccination programme to suppress the spread of infection and prevent disease.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is persisting endemically in the UK with long-term implications for public health planning and preparedness. As at 2nd June 2022, 73% of the Scottish population aged 12 and over have received three doses of COVID-19 vaccine6. Although we note that large and frequent COVID-19 clusters are also associated with settings involving older adults such as leisure, sporting events, and occupation9.With the exception of the first SARS-CoV-2 epidemic wave in 2020, cases among children, adolescents, and young adults have represented a high fraction of confirmed cases in Scotland. Younger age groups may contribute to seasonal patterns of COVID-19 in the long-term, with annual outbreaks in educational settings a well-recognised feature of acute respiratory infections in temperate climates10. Universities present a unique epidemiological scenario for study, with the movement of students to and from domicile locations at the start and end of academic terms presenting a risk for introducing viruses into student populations and for spillover into local communities11. Theoretical models suggest that SARS-CoV-2 will more easily transmit in denser populations depending on vaccination rates, adherence to social distancing, and effectiveness of contact tracing and isolation measures13. With a potential increased likelihood of asymptomatic infection14 and lower vaccination coverage1, student populations are at risk of seeding outbreaks among their social groups as well as exposing the local community and non-term-time contacts. Reports highlighted the potential for a large number of cases in higher education settings, particularly in association with densely populated residential halls16.With respect to higher education settings, the risk of respiratory infection outbreaks have been brought to the forefront by COVID-19, with the implementation of social distancing and remote learning to limit cases18 and care homes19. To date one study in the UK has taken such an approach to understand SARS-CoV-2 outbreaks in a tertiary education setting15. This study identified persistent transmission among students, though with little evidence of transmission to the local community. However, the social and community contexts of universities in the UK differ, such that patterns of spread within a collegiate university, a single institution organised into self-governing colleges with associated accommodation, may not be directly applicable to universities with a more centralised organisational structure.Expansive SARS-CoV-2 genomic surveillance conducted in the UK, with over 300,000 whole genome sequences generated by June 2022 in Scotland alone, provides a means to characterise outbreak risks in a setting-specific manner. In combination with epidemiological data, genomic surveillance has enabled fine-grain characterisation of SARS-CoV-2 outbreaks in other semi-closed settings such as hospital wards20. At this point reported case numbers were relatively low, although with the second epidemic wave in Scotland already underway21. Our study provides a genomically-informed insight into epidemiological risks associated with SARS-CoV-2 outbreaks in a university accommodation setting in which students were resident in halls integrated with the local community in the city of Glasgow.Here we use genomic epidemiology to investigate a large cluster of cases among University of Glasgow (UoG) students in Scotland, UK, arising in the autumn of 2020 at the start of the 2020/21 academic year1, and in the event of a novel SARS-CoV-2 variant of concern, there is a need for public health planning and policy formation to consider the higher educational setting, particularly in preparation for winter seasons. We propose that consideration is given to the varying accommodation, academic, and social contexts across student populations.Our study contributes to a comprehensive understanding of the role that residential accommodation can play in the spread of SARS-CoV-2, and highlights the success of rapidly implemented control measures on mitigating any subsequent impact on the wider university population and the local community. Given the current lower 3rd dose vaccine uptake among young adults in Scotland (as at June 2022)22. The university provides multiple residential halls predominantly housing undergraduate students23.As of the 2020/21 academic year, the UoG hosts approximately 33,000 students from more than 140 countries, with 97% of undergraduate students aged 16–29 years, and with 58% of the 6100 new undergraduate students domiciled in ScotlandA cluster of COVID-19 student cases associated with two geographically distinct residential halls was identified by the UoG and the NHS Greater Glasgow and Clyde (NHSGGC) Public Health Protection Unit at the start of the 2020/21 academic year, immediately following Freshers’ week (12th to 18th September)  had respiratory specimen dates from 19th September to 26th September 2020 spanning the residential halls cluster. Based on these data, the student cluster included around 9% of the new undergraduate population overall. SARS-CoV-2 whole genome sequences were available for 220 cases, with specimen dates spanning 5th September to 18th November 2020; 73.2% were from students residing in university residential halls with specimen dates from 19th September to 26th September 2020  resident at one of six university residential halls spanning 13 postcode locations. The remaining 423 (40.7%) students were deemed to reside in private accommodation see “”. The me26 were detected ted Fig. c, the moted Fig. d.17. We use the term ‘transmission cluster’ to denote a set of potentially linked cases consistent with having arisen from a single introduction into the student population , and private accommodation (5 cases), were genetically indistinguishable from sequences identified from outbreaks associated with six other Scottish universities  showed a rise in cases among adults aged 17–24 years coinciding with the start of the UoG residential halls cluster Fig. . FurtherWe combined genome sequence data with epidemiological information to investigate a cluster of COVID-19 cases associated with UoG student residential halls. These cases occurred prior to rollout of the UK’s COVID-19 vaccination programme and the use of lateral flow device tests for regular asymptomatic self-testing by the students. We evaluated frequency and origins of SARS-CoV-2 introductions into the student population, the likelihood of transmission among the students, and impact on the local community. The integration of genomic, evolutionary, and epidemiological approaches provides a deep insight into the nature of viral spread within a university accommodation context.27.Our study highlights several important features of public health significance. Firstly, the increase in SARS-CoV-2 infections among the student population primarily involved university accommodation. The sudden rise in student cases emerged shortly after social events linked to “Freshers’ week” at the start of the university term, providing a strong indication that the outbreaks spread via induction events and/or other social activity and gatherings28. Although the sequencing of UoG student cases was incomplete, with around 30% coverage of the residential halls cluster, we can be reasonably confident that all major transmission clusters were detected.Secondly, while there was evidence of at least 11 introductions of SARS-CoV-2 into the university student population, our data were consistent with only four leading to substantial onward transmission among students, each consistent with a separate outbreak. Our data suggests the presence of large variations in the numbers of individuals infected by each introduction, potentially attributable to superspreading events whereby a small number of individuals cause a disproportionate number of cases29. The risk of importing SARS-CoV-2 from countries outside of the UK was not directly addressed by our study owing to a lack of robust data at a global level.Thirdly, the data were strongly indicative of introductions into the university from Scotland for at least two of the four clades. Our findings highlight that although the potential for virus importations into Scotland through long-distance student movements remains, the risk of new variants being introduced to Scotland at the start of the academic year would appear low in comparison to other UK regions given the high proportion of Scottish students domiciled within Scotland23. The identified transmission clusters were consistent with student–student transmission linked to household-like conditions and/or shared facilities within residential halls. Social gatherings may also be a conduit for the apparent transmission between households and likely contributed to the multiple viral populations within halls, with mixing of individuals returning to the university from various locations, and with compliance to social distancing expected to be poor at such events.Fourthly, our study highlights the rapid spread of SARS-CoV-2 within and between university accommodation. Halls of residence provide household-like conditions enabling direct and indirect transmission of SARS-CoV-2 via respiratory (aerosol and droplet) and fomite routes. Accommodation at the UoG comprises predominantly off-campus accommodation, representing a mixture of self-contained flats, shared kitchen spaces and bathroom facilities, and common room/study areasDespite the scale and speed at which the outbreak grew, the rapid curtailment of the outbreaks demonstrates that the swift action of the university and local Public Health Protection Unit, together with an apparent high degree of student compliance, prevented any further rise in case numbers and limited any impact on the local community. We note that a decline in proportional sequencing coverage in Scotland in the period subsequent to the UoG outbreaks (from an average daily coverage of ~ 24% in September 2020 to ~ 4% from mid-October 2020) limits the ability to detect associated variants circulating at low prevalence, and precludes a direct comparison of observed clade-specific case incidence rates between Scotland and England. However, we can be reasonably confident that variants associated with any significant outbreaks or long-lasting chains of transmission would be detectable among the community sequences available, given that sequencing was conducted daily over an extended time frame. It is likely that self-isolation by students was the predominant factor leading to the rapid end of the student halls-associated outbreaks, although our study did not formally evaluate control measure effectiveness.30 in the absence of university closures and restriction of social activities. This period saw a decreasing case incidence nationally alongside the accumulation of immune protection via vaccination and naturally-acquired immunity, and with the introduction of self-testing by asymptomatic students using lateral flow device tests31. The opening of educational settings during periods of low incidence may be an important component of risk mitigation32, alongside promotion of safer socialisation practices and enhanced social care and support structures33.At the time of the UoG outbreaks, most educational institutes in the UK had undergone emergency closure of in-person teaching in response to the COVID-19 epidemic, resulting in prolonged periods of remote learning. However, significant outbreaks arose in the university setting, albeit during a period of relatively high susceptibility and prior to rollout of the national vaccination programme. In contrast to 2020/21, numbers of university student cases were comparatively lower in Scotland at the start of the 2021/22 academic year15. UoC is an atypical UK higher educational institution in that in addition to education, accommodation and the social setting among students revolves around independent colleges. By contrast, UoG is far more centralised and integrated, albeit with university accommodation being more geographically intertwined with the local community. In Cambridge, the outbreak was dominated by a single large cluster that persisted until the national lockdown in November 2020. That the UoG residential halls were geographically restricted likely enabled greater control and enforcement of isolation measures through provision of student support. The outbreaks associated with UoG did however show greater interaction between students and the broader community than observed for UoC, with community and student cases in the largest clade being substantially mixed. The contrasting findings across studies provides invaluable context in understanding the role of SARS-CoV-2 spread within the university setting. Differences in university organisation and housing structure are likely to have a pronounced impact on the potential spread of respiratory viruses, and the physical location of students within a city can affect both the nature and impact of an outbreak.The results from our study contrast with those reported for an outbreak among students at the University of Cambridge (UoC)Our study has some important limitations. Firstly, a comparison of infection risks associated with student social activities, or the household conditions and/or shared facilities within residential halls, was not possible. Secondly, interpretation of direct student-to-student transmission events is limited by lack of information on how sequenced cases were linked to individual households within a residential hall, and the low levels of variation in SARS-CoV-2 genomes make it difficult to conclusively define epidemiological links. Thirdly, the analysis of the origins of the university student associated clades does not consider the potential for the introduction of cases into the student population via international travel. Fourthly, it is possible that some student cases were misclassified as community cases. Fifth, we note that the presence, frequency and diversity of SARS-CoV-2 may be biased by the targeted sampling of outbreaks, particularly during periods of low sequencing coverage. Some targeted sequencing of the UoG student outbreak had occurred to assist with initial investigations in near real-time. Finally, only 30% of identified student cases were sequenced. We have aimed to provide conservative estimates throughout.These analyses have provided valuable insight into a large outbreak in an off-campus university accommodation setting, and an evidence base to inform future policy recommendations for students returning to universities at the start of terms. The higher education setting presents a risk for contributing to the winter burden of COVID-19. With rapid identification, and implementation of non-pharmaceutical control interventions, the impact of outbreaks on local communities may be limited. However, while high rates of vaccination have moderated the impact of SARS-CoV-2 disease severity on the UK population, it is clear SARS-CoV-2 will continue to evolve in the human population such that student populations, as with all demographics, should be encouraged to be up to date with vaccinations (currently three doses in under 75 year olds as of mid-2022).20).A retrospective search was performed in a database of NHS Scotland Test and Protect contact tracing interviews, known as the Case Management System. The case definition pertaining to a University of Glasgow (UoG) associated student was applied as follows: the text “Glasgow” and “university or uni” under occupation related fields, and with RT-PCR diagnostic test confirmation of a SARS-CoV-2 infection between 1st September 2020 and 30th November 2020. Free text notes were inspected and cases were excluded if determined to not be a University of Glasgow student. Residential postcodes were then matched to UoG student halls postcodes obtained from the Scottish Government Advanced Learning and Skills Analysis (ALSA), identifying cases resident in university accommodation. Further cross checking was performed: student status was corroborated by the individual’s age (with the majority of student cases ≤ 19 years) and/or an additional interrogation of free text notes. Four cases had missing age information. We note that our approach is relatively conservative, and the number of student cases identified may differ from that based on other methods  partnership laboratories at the MRC-University of Glasgow Centre for Virus Research and Sanger Institute for sequencing. The genomic sequence data were uploaded to CLIMB -COVID17. Given symptom onset dates and SARS-CoV-2 genome sequences from multiple individuals, this carries out a series of hypothesis tests, calculating whether the data from each pair of individuals A and B is statistically consistent with a model of A having directly infected B; data are assessed as being consistent with transmission, borderline, or unlikely to have arisen from a direct transmission event. Our model utilises distributions for the infectivity profile and time to symptom onset described for SARS-CoV-2 by other publications37. In the absence of symptom onset dates, respiratory specimen collection dates were used as proxy estimates. A sub-setting procedure was used to generate putative transmission clusters, placing two individuals in the same cluster if transmission between those two individuals in either direction was not unlikely.Putative transmission clusters were inferred using the A2B-COVID software package38 in order to characterise the transmission clusters in terms of phylogenetic clades. Inferences used ModelFinder to identify the most appropriate model in each case39. The trees of Figs. Phylogenetic inference of UoG student sequences was then conducted using the IQ-Tree2 packageS,C and gE,C were the number of virus genome sequences in clade C collected in Scotland and England respectively, during the two weeks prior to the first observation of the clade in students at the UoG, while GS and GE were the total number of virus genome sequences collected in Scotland and England during the same period.The sampling locations of sequences in each clade were used to determine the likely origin of each transmission cluster. Viral genome sequence data were then used to estimate the probability that each of the four major clades we identified arose from an introduction into the student population either from England or Scotland. To derive an estimate of the probability that the introduction of a clade C came from England, we first estimated the fraction of genome sequences of clade C in England and Scotland in the two weeks prior to the observation of the first student case in that clade:S,C and PE,C that a given individual in either Scotland or England respectively was infected with SARS-CoV-2 from clade C:S and IE were the mean total numbers of positive tests reported per week in Scotland and England during the 2 weeks in question, as reported in UK Government statistics40, while NS and NE are ONS mid-2020 population estimates for Scotland and England41. Given these values, we estimated the probability that a student arriving in Glasgow was infected with SARS-CoV-2 of clade C and domiciled in either Scotland  or England . For XS,C this is given byS,U and PE,U are the probabilities that a given student at UoG was domiciled in Scotland or England respectively. The equivalent value XE,C that the student was domiciled in England is given by XE,C = 1 − XS,C.Using these values, we estimated the prevalence of each clade in Scotland and England to inform the probabilities PIn our calculation we neglected the possibility of introductions from outside of either England or Scotland due to the lack of data from other locations. Our measure is approximate, being prone to sampling bias and limited data, but was used to provide a broad indication of the geographical origins of clades.42 was then used for extracting the smallest phylogenetic clade containing the sequences in each putative transmission cluster. This was used to put the SARS-CoV-2 genome sequences from UoG students in the broader context of UK wide sequences. The clades were pruned to include only sequences from UoG students and NHSGGC and students from other Scottish Universities determined through contact tracing. For visualisation of these clades, identical sequences were collapsed and the figure was produced in The Environment for Tree Exploration43.The COG-UK phylogeny for SARS-CoV-2 was produced using CLIMB-COVID data available on the 2020–12-31. The grapevine pipelineAll individuals with respiratory specimens collected for diagnostic testing of SARS-CoV-2 infections by RT-PCR in Scotland between 1st September 2020 and 30th November 2020 were identified from the national Electronic Communication of Surveillance in Scotland (ECOSS) database. Age-stratified 7-day rolling proportions of SARS-CoV-2 positive cases, among all RT-PCR-tested individuals, were estimated for the City of Glasgow, excluding cases with residential postcodes associated with UoG residential halls, in a conservative approach to removing the influence of UoG students from the analysis. A comparison was made with the rest of Scotland, excluding individuals resident in the City of Glasgow. The 17–24 years group represent the age range of the UoG residential halls-associated cases.https://www.informationgovernance.scot.nhs.uk/covid-19-privacy-statement/), including the Civil Contingencies Act 2004, the NHS (Scotland) Act 1978 and the Public Health (Scotland) Act 2008, and under Articles 6(1)(e), 9(2)(h), 9(2)(i), 9(2)(j) of the General Data Protection Regulation. Surveillance data was shared with NHS Scotland according to the Intra NHS Scotland Data Sharing Accord (https://www.informationgovernance.scot.nhs.uk/wp-content/uploads/2020/06/2020-06-17-Intra-NHS-Scotland-Sharing-Accord-v2.0.pdf). Ethics approval was not required for this work which was based on pre-existing routine surveillance data for the Scottish population.This study was undertaken as part of public health surveillance activity within the COVID-19 programme of Public Health Scotland, in line with the necessary associated regulations and guidelines. The retention and processing of information on individuals is conducted by Public Health Scotland as part of COVID-19 surveillance in Scotland in the context of emergency data processing (Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.


Odor detection and discrimination in mammals is known to be initiated by membrane-bound G-protein-coupled receptors (GPCRs). The role that the lipid membrane may play in odor discrimination, however, is less well understood. Here, we used model membrane systems to test the hypothesis that phospholipid bilayer membranes may be capable of odor discrimination. The effect of S-carvone, R-carvone, and racemic lilial on the model membrane systems was investigated. The odorants were found to affect the fluidity of supported lipid bilayers as measured by fluorescence recovery after photobleaching (FRAP). The effect of odorants on surface-supported lipid multilayer microarrays of different dimensions was also investigated. The lipid multilayer micro- and nanostructure was highly sensitive to exposure to these odorants. Fluorescently-labeled lipid multilayer droplets of 5-micron diameter were more responsive to these odorants than ethanol controls. Arrays of lipid multilayer diffraction gratings distinguished S-carvone from R-carvone in an artificial nose assay. Our results suggest that lipid bilayer membranes may play a role in odorant discrimination and molecular recognition in general. Odor detection in mammals is initiated in cellular membranes that contain well-studied G-protein-coupled receptors (GPCRs) ,2,3,4,5.In a number of cases, membrane composition and structure are thought to regulate membrane protein activity ,27. MechChemically, odorants tend to be relatively small hydrophobic compounds . This isModel membrane systems such as vesicles and supported lipid bilayers are well established for studying the behavior of lipid bilayers in vitro ,44,45,46In the case of lipid multilayer gratings, nanoscale heights and optically efficient periodicity along the wavelength of light can be patterned onto a surface, and diffraction intensity can be monitored from the lipid grating as a function of time for measuring and modeling of analyte activity ,54,55. LLipid micro- and nano-structured droplets have formed on surfaces by dip-pen nanolithography ,59,60,61Lipid multilayer substrate preparation: Lipid multilayers of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) doped with one mol percent rhodamine-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl)  (rhodamine-PE) were arrayed onto a clean glass surface using a polymeric stamp of either dots or gratings. As confirmed previously by atomic force microscopy, the dot lipid multilayers were around 250 nm in height and 5 µm in diameter, while the lipid gratings had 700 nm periodicity and sub-100 nm heights. They were immersed in deionized water, and then odorants were introduced in solution by reverse pipetting. A concentration of 1 µM carvone enantiomers  caused disruption of pattern fidelity and dissolution compared with the application of ethanol at the same concentration on a different sample. Chemical structures were rendered using ChemDraw Pro v.8 for Windows and Powerpoint.Fluorescence recovery after photobleaching (FRAP): The purpose of FRAP on surface-supported lipid bilayers is to indicate a change in the recovery of the membrane (a measure of fluidity of the membrane) after exposure to the odorant. Due to carvone enantiomer’s low solubility in water, solutions were administered in a distilled water solution of 0.5% DMSO. DOPC with one mol percent Rhodamine-PE supported lipid bilayers were prepared using a vesicle fusion method by washing sonicated vesicles in deionized water (pH 7) with 1 M Ca2+ ions on an oxygen-plasma-coated glass slide . Applying vesicles onto the surface with Ca2+ ions in solution and then washing caused the rupturing of vesicles onto the surface whereby the wash steps removed the excess Ca2+.Nanointaglio printing: Lipid multilayer dots and gratings were fabricated by nanointaglio [intaglio . Dehydraintaglio ,64. The Lipid pattern storage: After nanointaglio fabrication, lipid gratings and dots were stored in a nitrogen glovebox  Stratham, NH, USA) for 24 h to remove all water or to dehydrate them. The nitrogen environment stabilized the lyotropic lipid multilayer nanostructures by dehydration prior to immersion in water [in water . After iLipid multilayer gratings vapor chamber: Lipid multilayer gratings were arrayed onto 100 mm diameter polystyrene petri dishes. The gratings were stabilized in a set position using double-sided tape, then characterized using a diffraction light setup for a baseline control before odorant addition. We deposited 200 µL of carvone enantiomer (Sigma Aldrich) on a chem wipe into the corner of the chamber, and then the chamber was immediately sealed from the outside with Parafilm. Once sealed, diffraction images were taken every five seconds. Choosing time points at 20 and 40 s after odorant application enabled measurement of lipid multilayer responses to the odorants, which then allowed us to generate a point in principal components analysis (PCA). One hundred-pixel regions of interest (ROI)s were chosen from each of the six lipid grating formulations and used for the analysis. Three different samples were used for each carvone enantiomer. PCA was executed on the diffraction gratings as described previously [eviously  using OrThe chemical structures of the lipids and odorants used here are shown in −5 M and S-carvone 10−3 M when compared with the R-enantiomers at those concentrations. Since the diffusion of unbleached molecules continues during bleaching, this suggests that S-carvone decreases the fluidity of the bilayer compared with R-carvone at these concentrations. Surprisingly, this effect does not appear at the higher concentration (10−1 M). A possible explanation is that the lipid bilayer chirality interacts more with the S-enantiomer than the R-enantiomer to cause a decrease in the membrane exchange (lower fluorescence intensity) of the region outside membrane exposure, thus indicating differences in membrane fluidity at specific concentrations. Based on qualitative observation, the data suggest the concentration of carvone enantiomers may impact the fluidity of lipid bilayers differently, depending upon the enantiomer used. Specifically, there is a larger difference in the bleaching intensity for S-carvone 10We then tested the effect of odorant solutions on lipid multilayer droplet arrays immersed in water. Arrays were fabricated by nanointaglio as shown with examples in The experimental setup is depicted in −3 M and lower, indicating less pattern disruption for R-carvone at lower concentrations than for S-carvone. This unique concentration dependence is consistent with what was observed in the FRAP data  of phospholipids printed onto the surface and exposed to carvone enantiomer vapor (three experiments for each enantiomer) are shown in −3 M and lower. One possible explanation could be based on the incorporation of the S-enantiomer into the lipid membrane based upon the chirality of both molecules. It is somewhat surprising that a difference between two enantiomers was reproducibly observed at lower concentrations but not higher concentrations. Dose–response effects in biological systems typically become stronger at higher concentrations [The results presented here suggest that the lipid membrane may play a modulatory role in odorant discrimination. Given the kinetics of the lipid multilayer responses to the carvone enantiomers, lipid membranes may also serve a secondary function for odorant adaptation. FRAP and lipid multilayer assays demonstrated significant changes in bilayer properties upon exposure to odorants. In several cases, a marked difference between enantiomers was observed when comparing S-carvone and R-carvone, specifically at concentrations of 10trations . The lipThe implications for odor recognition in vitro are that the supramolecular structure of lipid bilayer membranes in the olfactory epithelium may play a role in the signal detection and transduction process. Possible explanations for how an odorant could interact with the lipid membrane in order to help concentrate and enable the odor receptor to bind the odor are presented in The possibility that the partitioning of a ligand into a lipid bilayer may trigger a pathway such as GPCR activation is a new way of thinking about receptors and membranes. Like odorants, many drugs tend to be lipophilic, and lipophilic drugs tend to be more potent than more polar drugs . Further


Burnout is common among residents, which could be associated with their professional network characteristics. This study aimed to assess the social networks of psychiatry residents and develop an intervention to improve their network characteristics, burnout, and perception of the educational environment.We recruited a cohort of 17 PGY-2 residents and assessed their social networks, burnout, and perception of the educational environment. After the baseline survey, we held a focus group with PGY-2 residents to discuss the results, their network characteristics, and interventions that can improve their relationships. The PGY-2 residents indicated that offering extracurricular opportunities to facilitate friendly interactions among the residents and faculty members would be the most feasible and acceptable intervention. Therefore, four “interest groups” for extracurricular activities were established. Residents and faculty members were invited to participate in interest groups to improve the network characteristics. Some PGY-2 residents and faculty members agreed to moderate interest group sessions (active members).After the intervention, active residents improved significantly in the perceived personal accomplishment subscale of the burnout inventory and their perception of the educational environment. Active faculty members also had a significant increase in their relationships with PGY-2 residents in one domain of social networks.Enhancing relationships between residents and faculty members through participatory intervention and extracurricular activities can improve faculty-resident connectivity and residents’ perception of personal accomplishment and educational environment quality.The online version contains supplementary material available at 10.1186/s12909-022-03440-5. Teaching hospitals are multi-purpose communities with different, and often conflicting, aims: providing quality care, conducting health research, and training competent physicians. In this environment, the well-being, burnout, and academic performance of residents, given their dual responsibility both as a physician and a trainee, is a matter of concern . These cSocial network analysis (SNA) research has investigated the effect of social contagion and influence on different aspects of life . PersonaIn health system research, SNA has indicated that network characteristics of the staff are associated with burnout and job satisfaction , 14. In In this study, we aimed to elicit the social network of a class of residents in an academic psychiatric hospital (Roozbeh) in Tehran, Iran. We also intended to develop and implement a participatory intervention informed by network analysis to improve residents’ burnout and their perception of the educational environment.The physician community of the hospital consists of faculty members and psychiatry residents. Between 16 and 20 physicians start their psychiatry residency program at the hospital each year. The psychiatry residency is a four-year, competency-based program with a combination of supervised clinical experiences in different settings and a comprehensive didactic program. The pillars of the residency curriculum are quite similar to most North American programs. The resident-faculty relationship is usually limited to clinical settings, seminars, journal clubs, and other didactic sessions.The baseline survey took place in December 2018. At the time, the hospital physician network consisted of 17 PGY-2 residents (participants), 34 PGY-3 and PGY-4 residents, and 47 faculty members. The follow-up survey took place in January 2020. The PGY-2 residents completed the study questionnaire at baseline and follow-up, which included the social networks questionnaire, the Maslach Burnout Inventory (MBI), and the Postgraduate Hospital Educational Environment Measure (PHEEM).To assess the social networks and develop the intervention, we approached PGY-2 residents because they had already spent a year together building some relationships and had enough time ahead to get engaged in an intervention. PGY-2 residents were asked to nominate other residents and faculty members from a roster of hospital physicians with whom they had a social relationship in three different domains  in the previous month.The survey also included the Maslach Burnout Inventory (MBI)  and the The intervention was designed in a participatory manner. After the baseline survey and data extraction, we held a focus group with the PGY-2 residents. Fifteen out of 17 PGY-2 residents attended the focus group. The network maps and a brief report on burnout levels and PHEEM scores were presented to the PGY-2 residents. The PGY-2 residents were asked to brainstorm about the networks and interventions that can improve their relationship and perceived support.According to the PGY-2 residents, their networks with each other were acceptably dense and balanced and needed no intervention. They also felt they had enough access to senior residents, and the amount of interaction was satisfactory. However, the PGY-2 residents felt a need for more interaction with faculty members, especially in a more informal manner. After more discussion about network characteristics, PGY-2 residents extensively reviewed potential solutions. PGY-2 residents indicated that offering extracurricular opportunities to facilitate friendly interactions among residents and faculty members would be the most feasible and acceptable intervention. Therefore, four “interest groups” focusing on extracurricular activities  were established, and residents and faculty members were invited to participate. There was no limitation on the number of interest groups that residents and faculty members could attend.To ensure appropriate management of the interest groups, one or two volunteer PGY-2 residents and one or two faculty members were assigned to moderate each interest group. This group will be called “active PGY-2 residents” and “active faculty members”, collectively called “active members”. The non-active members were also invited to and could attend all interest groups’ meetings; the only difference was involvement in interest groups’ moderation. Seven PGY-2 residents and six faculty members volunteered to serve as active members. Each interest group was expected to hold one meeting per month. The investigators did not intervene in the interest group’s management. During the seven-month intervention period, three interest groups held six meetings each, and one held five meetings.The network maps and indicators were created using UCINET software . Two groWe calculated the following indicators of the network structure: density , reciprocity , and indegree centralization . The significance of network structure differences between baseline and follow-up was calculated via bootstrap t test with 5000 samples using UCINET software.We developed mixed-effect linear regression models with restricted maximum likelihood ratios to assess the changes in outcomes . For each model, the predictors included the “active vs. non-active members” and a variable indicating “baseline vs. follow-up” and their interaction. In models assessing PGY-2 residents’ changes, the PGY-2 resident’s ID number and in the models assessing faculty members’ changes, the faculty member’s ID number, were considered as the random effect. The models were developed by the “lme4” and “lmeTest” packages of R software version 4.03 , 27.All 17 PGY-2 residents agreed to participate in the study . The median age of PGY-2 residents was 32 years. One was excluded from the study because of failing the annual evaluation exam resulting in a different educational trajectory at follow-up.Figure At follow-up, the densities slightly decreased, which was statistically significant in the personal support network. In all three networks, we observed a decrease in reciprocity and a mild elevation in indegree centralization, implying a tendency towards hierarchy.The difference in interest group attendance between active and non-active members was significant for both PGY-2 residents and faculty members . Non-active PGY-2 residents, on average, attended 1.3 sessions, while active PGY-2 residents attended eight sessions. Similarly, the average attendance for non-active faculty members was 0.7 sessions, and for active faculty members was 6.8 sessions.Active PGY-2 residents did not differ from other PGY-2 residents in any network properties at baseline . After seven months of the intervention, we found that the intervention significantly increased the relationships of active faculty members with PGY-2 residents and improved burnout and perception of the educational environment in active PGY-2 residents.The results show that the intervention was particularly beneficial for active PGY-2 residents, who had an improved perception of personal accomplishment at follow-up. This finding is in concordance with a published cross-sectional study indicating that out of burnout sub-scales, only perception of personal accomplishment is associated with social network position . InteresActive PGY-2 residents also reported an improved perception of the educational environment. This finding is in line with existing literature. We know that while faculty-student relationships affect students’ performance, they are usually scarce and limited to academic interactions . StudiesUnlike their peers, non-active PGY-2 residents reported significantly higher emotional exhaustion and a declining perception of personal accomplishment and of the educational environment quality. During the intervention period, several stressful events happened in the country, such as a serious economic crisis that posed stress to the public and might have contributed to this higher burnout in non-active PGY-2 residents. But it is also possible that the intervention design per se could be partly responsible for the unfavorable outcome observed in non-active PGY-2 residents. A similar pattern was seen in another study aimed to improve self-care behavior in residents by an intervention involving some residents and informing other residents about their progress via email, hypothesizing that the emails would improve other residents’ self-care by social contagion. The authors found that other residents who were not directly involved in the intervention neither welcomed nor benefited from emails . The resThe intervention successfully increased the relationships of active faculty members with PGY-2 residents. At follow-up, active faculty members had a significant increase in their relationships with PGY-2 residents at the personal support network. Although, this improvement did not extend to the non-active faculty members’ relationships. It is not unusual in social network studies that interventions impact actors differently. The concept of preferential attachment suggests that the actors with more social ties have more chance of developing new ties due to intervention, a phenomenon that results in a “rich get richer” pattern after network interventions . This imAt the time of preparing this manuscript (one year after follow-up surveys), three out of four interest groups are still running while investigators had no contribution to it. The interest groups survived the COVID-19 pandemic by using online interfaces. This indicates that the effects of the intervention may have gone beyond what we have reported here.We faced some limitations in our study, namely, the quasi-experimental design without a control group which was implemented in a real-life environment. There were numerous confounding variables that we were unable to control. Therefore, the conclusions we made in this manuscript are merely hypotheses in need of further confirmation in controlled interventional studies. Our small sample size limits the statistical power of the study. Furthermore, we did not assess the quality (frequency and intensity) of relationships, which may have changed due to intervention.Enhancing relationships between residents and faculty members through participatory intervention and extracurricular activities can improve faculty-resident connectivity and residents’ perception of personal accomplishment and of the educational environment quality.Additional file 1.


The purpose of this study was to evaluate the effect of coronal restorations on the survival rates against fracture of endodontically treated premolars with exposed cervical lesions and to identify the prognostic factors for fracture.Data of the endodontically treated premolars with exposed cervical lesions restored with resin composites or crowns between 2011 and 2020 were collected. The presence of a fracture was recorded, and the possible prognostic factors were recorded. Statistical analyses were performed, with a significance level of P<0.05, using a Kaplan-Meier survival analysis, log-rank tests, and Cox proportional hazard models were used to identify the prognostic factors.The survival rates against fracture were not significantly different between the teeth restored with crowns (93.3%) or resin composites (86%) (P≥0.05). A high frequency of non-restorable fractures was observed in both groups. Crestal bone reduction to the middle-third of the root was identified as the significant prognostic factor (P<0.05).For endodontically treated premolars with exposed cervical lesions, resin composite restorations provided a high comparable survival rate that was comparable to that of crowns. A higher risk of fracture was found in endodontically treated premolars with crestal bone loss to the middle-third of the root. Thus, the supporting periodontal tissues should be well-maintained to prevent a decrease in the bone level that increases the risk of fracture.The clinical success of endodontic treatment significantly improves when the tooth recieves a coronal restoration that prevents coronal leakage and protects the remaining tooth structure from fracture , 2. EndoEndodontically treated posterior teeth restored with full coverage crowns display a significantly lower fracture incidence than those restored with resin composites . HoweverA cervical lesion refers to the loss of cervical tooth structure on the buccal or lingual surface due to root caries or tooth abrasion. The cervical cavity generates high stress that is concentrated at the cervical region, especially at the pulpal floor of the cavity -10. As tA cervical fracture can occur in ETT with exposed cervical lesions and due to this concern, many dentists typically choose a full-coverage crown compared with a resin composite restoration. However, this preference lacks supporting clinical evidence. In a laboratory study by Machado et al. (2017),  the fracIt remains unclear whether the type of coronal restoration, particularly crown and resin composite, affect the survival against fracture of endodontically treated premolars with exposed cervical lesions. Moreover, the prognostic factors affecting survival have not been previously reported. Therefore, the aim of this retrospective cohort study was to compare the survival rates against fracture of endodontically treated premolars with exposed cervical lesions that were restored with either a crown or resin composite. In addition, the significant prognostic factors for fracture were identified.The protocol for this retrospective cohort study was approved by the Ethical Review Committee for Human Research Office of the Faculty of Dentistry and Faculty of Pharmacy, Mahidol University, Bangkok, Thailand (MU-DT/PY-IRB 2020/DT011). Informed consent was not required due to the retrospective nature of the study. Data was collected from the dental records and radiographs of premolars receiving endodontic treatment at the Endodontic Clinic, Faculty of Dentistry, Mahidol University, and the patients were recalled between January 2011 and June 2020. The post-endodontic coronal restorations, either full-coverage crowns or resin composites, were provided by undergraduate, postgraduate, or restorative dentists. The subjects were recruited according to the following criteria.The inclusion criteria were endodontically treated premolars  with expThe exclusion criteria were the teeth with  endodontThe following data were recorded: the sex, age, tooth location, location and height of the exposed cervical lesion, type of coronal restoration, functioned as an abutment for a prosthesis, an opposing tooth, posterior tooth support, proximal contact(s), level of bone support, and parafunctional habits. In addition, the presence of a fracture was determined, and the fracture location and the restorability were recorded.For the endodontic treatment, conservative access openings were performed under dental dam isolation. The root canal preparation was performed with stainless steel hand files  or rotary nickel-titanium files  and irrigated with 2.5% sodium hypochlorite and 17% EDTA. A water-based calcium hydroxide intracanal medicament was used for at least 1 to 2 weeks. The obturation technique was either lateral compaction (LC) or warm vertical compaction (WVC), based on the preference of the treatment providers, using gutta-percha and either a zinc oxide eugenol root canal sealer, MU Sealer  or an epoxy resin sealer, AH Plus (Dentsply). The gutta-percha was seared off and plugged into the canals ~1-3 mm below the cervical exposure site. The coronal access was filled with a temporary restoration.A post-endodontic coronal restoration, either direct resin composite or crown, was planned. For the premolars restored with resin composite as a permanent restoration, a 1-2 mm thick glass-ionomer cement (GIC) liner  was placed as an orifice barrier. The cavity was bonded with an etch-and-rinse  or self-etching  adhesive. The remainder of the cavity was filled with a nano-hybrid or micro-hybrid resin composite , which was light-cured for 20-40 sec for each layer. The centric and eccentric occlusal relationships were evaluated and adjusted before the restoration was finished and polished.For the premolars restored with crowns, a fibre-reinforced post  was tried and cemented into the prepared post space, with at least 4 mm of the gutta-percha remaining. The prefabricated post was cemented with a resin-based core build-up material . Then, either an all-ceramic or porcelain-fused-to-metal crown was fabricated and cemented using a self-adhesive resin cement .The occurance of tooth fracture was recorded. The primary outcomes were fractured or survived without fracture. Next, the fracture location was identified as a coronal, coronal-root, or root fracture. The fractures were finally categorised as restorable (repaired or replaced with a new restoration) or non-restorable (required tooth extraction).The data were statistically analysed using the Statistical Package for the Social Sciences (SPSS) version 22.0  with statistical significance set at P<0.05. The survival rates against fracture were compared between the teeth restored with crowns and those restored with resin composites with a log-rank test. The survival periods without fracture were analysed by a Kaplan-Meier survival analysis. Cox proportional hazard regression analysis was used to determine the association between the incidence of fracture and the prognostic factors with P≤0.20 in the univariate analysis.The endodontically treated teeth comprised 87 premolars from 77 patients  with ages between 24-87 years (mean 58.2±11.6 years) were included. In this study, 10 patients had 2 ETT, and the remainder (67) had one ETT. The teeth had exposed cervical lesions on the buccal side. Among the 87 ETT, 30 teeth were restored with full-coverage crowns, and 57 teeth were restored with resin composites. The follow-up periods were 37.5±15.0 months (14-60 months) for the teeth with crowns and 29.7±16.2 months (12-60 months) for the teeth with resin composite. The distribution of the factors based on the coronal restorations is presented in The overall survival rate of the premolars with exposed cervical lesions was 88.5% (77/87 teeth). The survival rate in the teeth with a crown was 93.3% (28/30 teeth), and 86% (49/57 teeth) for those restored with resin composite. The survival rates based on each factor are shown in The Kaplan-Meier cumulative survival curves  demonstrThe fractures found in the 2 teeth with crowns were a crown-root fracture and a vertical root fracture. Out of the 8 fractured teeth with resin composite restorations, 6 teeth had crown-root fractures and 2 teeth had vertical root fractures. All fractures (100%) in the premolars with crowns were non-restorable, whereas, 87.5% of the fractured premolars with resin composites were non-restorable. The univariable analysis revealed three potential prognostic factors that were further included in the multivariate analysis , which wThe present study compared the survival rates against fracture of endodontically treated premolars with exposed cervical lesions that were restored with either crowns or resin composites, and determined the prognostic factors for fracture. Within the 5-year observation period, the survival rates against fracture of the endodontically treated premolars with exposed cervical lesions were high and comparable between the teeth restored with crowns (93.3%) and resin composites (86%). To the best of our knowledge, this is the first clinical study to investigate the survival rate against the fracture of ETT with exposed cervical lesions. Our results suggested that the endodontically treated premolars could be conservatively restored with resin composite as the permanent restoration ; the plaAlthough similar survival rates were observed for the two restoration types, there are no prior clincial studies to compare our results with. However, our clinical findings corresponded with the results of a laboratory study, wherein comparable fracture resistance was observed between the endodontically treated premolars with exposed cervical lesions restored with all-ceramic crowns and resin composites .A cervical lesion generates high-stress that concentrates on the cervical region and changes the stress-strain pattern, which reduces the fracture resistance of ETT -13. HoweMore than half of the cases in this study had two adjacent teeth and no parafunctional habits, these conditions were favourable for the survival from fracture of the evaluated teeth. The proximal contacts of the adjacent teeth improve the survival rate against the fracture of ETT , 14, by Most patients included in this study were females, and a higher precentage of the females attended the follow-up compared with males. This studied population may be a confounding factor to the outcome because the occlusal force in females tends to be lower compared with males . HoweverIn our study, teeth with root canals prepared by hand and/or rotary files using the crown-down technique were included. The instrumentation provided a final taper between 4-6% and did not excessively remove root dentin or weaken the root structure. In addition, the different obturation methods, lateral and warm vertical compaction, may not influence whether a root-filled tooth fractures if the obturation was performed appropriately.The protocol for restoring ETT with resin composite was specific. All the teeth received a radicular extension of the resin composite, into approximately the coronal-third of the root canal, after 1-3 mm of the root canal filling below the canal orifice was removed. The primary goal of this protocol was to create an internal seal at the cervical exposure site to prevent coronal leakage into the filled root canal if any dislodgement of the cervical restoration occured. Furthermore, the radicular extension of the bonded restoration may improve the fracture strength of ETT by internal reinforcement, thereby reducing the chance of cervical fracture , 18. TheA crown-root fracture was most commonly found in the premolars with exposed cervical lesions. All fractures occurred at the cervical region where the lesion was located, leaving only a retained root. The restorability of the fractured ETT is then reduced, because the remaining tooth structure and its ferrule effect were limited. The absence of a ferrule compromises the prognosis and may lead to extraction of the fractured tooth; thus, it is critical for the longevity of ETT , 20. If In this study, a post was rarely placed in the cases restored with resin composite, while the crowned teeth were restored with a post. Most of the posts used in this study were prefabricated fibre posts that may provide a lower risk of non-restorable fracture compared with using a rigid cast post. However, the preparation of a post space tends to weaken the remaining root structure by further enlargement of the root canal. The fracture incidence of the crowned teeth with posts in our study was 6.7%.in vitro (The crestal bone level was the significant factor for survival against fracture. Compared with the normal crestal bone level at the cervical-third, the endodontically treated premolars with the bone support reduced to the middle-third of the root had a greater risk of tooth fracture. Previous clinical studies have reported the negative effect of the loss of bone support on the long-term survival of teeth , 23. Thein vitro . This isFor endodontically treated premolars with exposed cervical lesions, direct resin composite restorations with a radicular extension below the exposure site provided a high survival rate against fracture, comparable to that of crowns. Crestal bone loss to the middle-third of the root was a significant prognostic factor for tooth fracture.


Beyond its direct effects on physical health the COVID-19 pandemic has been shown to have negative effects on the living situation of people with severe mental illness (SMI). To date, there has been little research on resilience factors preventing people with SMI from experiencing negative effects of the COVID-19 pandemic.The objective of this study was to investigate the role of perceived empowerment (PE) as a resilience factor, preventing people with SMI from experiencing negative effects of the COVID-19 pandemic on daily living.We investigated negative effects of the COVID-19 pandemic on daily living in 931 persons with SMI at two times within six month between June 2020 and Mai 2021. To take into account the longitudinal structure of the data we applied mixed effects regression analyses and longitudinal path models.A majority of participants experienced negative effects of the COVID-19 pandemic on several dimensions of daily living. Negative effects increased with rising levels of illness-related impairment but decreased as the level of PE rose. While negative effects of the COVID-19 pandemic at follow-up were negatively associated with overall subjective quality of life baseline, PE was negatively associated with the negative impact of the pandemic and positively with quality of life.Patients with SMI need support to reduce negative effects of the COVID-19 pandemic on their quality of life. The promotion of PE could help strengthen resilience in this target group.DRKS00019086, registered on 3 January 2020. .German Clinical Trial Register,  The COVID-19 pandemic has significantly affected the quality of life of citizens all over the world. Even those who were not infected by the SARS CoV-II virus had to cope with the restrictions on personal freedom and public life . The psyAmong other vulnerable groups, persons with severe mental illness (SMI) have been expected by many experts to become particularly affected by the psychological distress caused by fear of infection, increasing social isolation, and restricted access to mental health care services –27. HoweIn order to develop and implement strategies to identify and support those patient groups with an increased risk of becoming negatively affected by restrictions and other challenges related to the COVID-19 pandemic, a stronger focus of research on potential resilience factors is needed . ConcernIn this investigation we want to answer the following research questions:How do patients with SMI perceive the COVID-19 pandemic having negative effects on different dimensions of their life?How is the experience of negative COVID-19 effects associated with socioeconomic and clinical characteristics?To what extent is change of the experience of negative effects of the COVID-19 pandemic moderated by PE and by functional impairment due to mental illness?How is the experience of negative effects of the COVID-19 pandemic associated with the patients’ subjective quality of life?The data of this investigation were collected as part of a multi-site randomized controlled trial (RCT) for the evaluation of an intervention providing a community psychiatric service intervention (GBV) for people with SMI in addition to care as usual (CAU). Details of the study have been published in the study protocol . This stDue to the COVID-19 pandemic the study onset had been postponed for 6 months from January 2020 to June 2020. In addition, the originally planned face-to-face assessment was changed to an internet based video interview with an online data collection. Only in cases where participants refused video interviewing or had not the technical requirements necessary for video interviewing, the assessment was conducted face-to-face.Study participants were recruited at 12 locations across Germany . PotentiThe “Health of the Nations Outcome Scale” (HoNOS) is an expert rating instrument to assess the impairment due to mental disorder on twelve dimensions including, agitated or aggressive behavior, depression, hallucination, self-impairment, substance abuse, cognitive capability, social relationships, daily living, accommodation, occupation and physical health –66. For The “Empowerment in Patients with Affective and Schizophrenia disorders scale” (EPAS) is a self-rating scale for the assessment of perceived empowerment at the dimensions daily living and occupation, social relationships, participation in the treatment process, sense of control and hopefulness ,68. OrigThe brief version of the “World Health Organization Quality of Life” instrument (WHOQOL-BREF) is a 24 item short version of the WHOQOL-100 which includes 100 items. The WHOQOL-BREF is a self-rating instrument assessing subjective quality of life at four dimensions physical health, psychological well-being, social relationships and environment and a global score including two items on perceived overall quality of life and overall satisfaction with health ,70. For The “Perceived Impact of COVID-19” scale (PICOV19) was developed for the purpose of assessing how our study participants perceived the impact of the pandemic on 9 dimensions: 1. Physical well-being; 2. cognitive functioning; 3. emotional wellbeing; 4. partnership; 5. social contacts; 6. financial situation; 7. housing situation; 8. mobility; 9. future expectations. For each of these dimensions participants were asked how the COVID-19 pandemic had affected it. The generation of the PICOV19 items was based on the assumption that the effects of lockdown measures implemented by the public health authorities to reduce infection risk could be perceived positively or negatively by patients with SMI. While negative effects could be expected due to limitations of usual activities and restrictions of individual freedom, positive effects could be expected by reducing daily hassles and the need for social interaction or having more time for family activities. Therefore, the answering categories for the items of the PICOV19 scale were 1 = very negative, 2 = negative, 3 = neither positive nor negative, 4 = positive, 5 = very positive. For the purpose of data analyses all items were reversely coded into negative direction. In addition to the analyses of the single items we generated a PICOV19 sum scores of the 9 items.For descriptive information on sample characteristics we computed means and standard deviations or absolute and relative frequencies. The internal consistency of the PICOV-19 was tested by means of Cronbach’s alpha. We also estimated means and 95% confidence intervals of the baseline and six-months follow-up (FU) assessments of the 9 dimensions and the total sum score (PICOV19) of the perceived impact of the COVID-19 pandemic on daily life.We computed mixed effects regression models for each of the 9 dimensions of the negative effects due to the COVID-19 pandemic and for the PICOV19 total scale. We included the following independent variables: SARS-CoV-2 infection status (yes vs. no); male gender (yes vs. no), age, partnership status (having a partner vs not having a partner); education (A-levels vs lower); monthly family income (6 categories in steps of 500 €); employment status (employed vs not employed); self-reported main ICD-10 diagnosis (dummy variables using F3 as reference category); EPAS total score; HoNOS total score; time (six-months FU vs. baseline assessment) and two interaction terms for time*EPAS and time*HoNOS.In order to analyze the impact of perceived negative effects of the COVID-19 pandemic on Quality of Life and the role of empowerment and illness severity in this process we generated a path model linking the baseline measures of empowerment  and impairment due to mental disorder  with the PICOV19 at baseline and six-months FU and with global quality of life (WHOQOL-BREF) at six-months FU. All path coefficients were controlled for sex, age, education, income, partnership status, employment status, current smoking status, body mass index (BMI) main ICD-10 diagnosis and if the patients reported a SARS-CoV II infection between baseline and six-months FU. Missing values were handled by using the full information maximum likelihood (FIML) estimator ,72. OverAs shown in As indicated by final mixed effects regression models see , the intCompared to participants with a diagnosis of an affective disorder, those with a schizophrenia spectrum disorder perceived less negative effects of the COVID-19 pandemic on their emotional well-being , partnership , social contacts , their financial situation , their mobility  and their future . Participants with a personality disorder perceived less severe negative effects than those with an affective disorder regarding their emotional well-being .Between baseline assessment and six-months FU, participants perceived increasing negative effects of the COVID-19 pandemic regarding their physical well-being , their emotional well-being , and their future .With increasing PE, participants perceived less negative effects of the COVID-19 pandemic regarding cognitive functioning , emotional well-being , their partnership , their social contacts , their housing situation  and their future .With increasing functional impairment due to mental illness, participants perceived increasing negative effects of the COVID-19 pandemic regarding their physical well-being , emotional well-being , housing situation  and their future .As indicated by the coefficient for the time*EPAS interaction term, increasing PE was related to a decreasing growth of perceived negative effects of the COVID-19 pandemic between baseline assessment and six-months FU, concerning physical well-being , cognitive functioning , emotional well-being , partnership , social contacts , housing situation , and future . The coefficients for the time*HoNOS interaction term indicated no significant moderation effect due to participants’ level of functional impairment.Cronbach’s alpha for the PICOV19 summary scale was estimated 0.75 at baseline and 0.77 at six-months FU indicating a sufficient reliability.The results of the mixed effects regression model for the PICOV19 total score see  indicateAs indicated by the standardized path coefficients presented in The decomposition of total direct and indirect effects revealed a total positive effect from empowerment at baseline to quality of life at a six-months FU  consisting of a direct effect  and a total indirect effect  which largely runs over the perception of a negative impact of the pandemic on the PICOV19 score six-months FU and over the combined effect of the PICOV19 score at baseline and at six-months FU. The total effect of the HoNOS baseline score to quality of life at a -six-months FU consists of the direct effect  and a total indirect effect  mainly running via the perception of a negative impact of the COVID-19 pandemic on the PICOV19 total score at baseline  and over the combined effect of the negative impact of the pandemic at baseline and at six-months FU .2 coefficients, the model explained 14% of the variance of the perceived negative impact of the COVID-19 pandemic measured by the PICOV19 score at baseline and 37.6% of the variance of the PICOV19 score at six-months FU and 36% of the variance of quality of life at six-months follow-up.As indicated by the R2 2.567 (p = 0.2771), RMSEA of 0.018 (95% CI = 0.000–0.071) with a probability of 79% to be < = 0.05; CFI = 0.999, TLI = 0.975 and SRMR = 0.005.The overall model fit parameter reveals a very good model fit with a nonsignificant ChiOverall, our study results confirm the hypothesis shared by many researchers that the negative consequences of the COVID-19 pandemic on people with mental disorders go far beyond the physical health impairments potentially caused by a SARS CoV-II infection ,19,21–27Our study results also suggest that PE, in the sense of a perceived control over key dimensions of life, represents an essential resource in people with SMI to cope with adversities of the COVID-19 pandemic. Increasing PE is associated with lower perception of negative effects of the COVID-19 pandemic on seven of the nine dimensions assessed with the PICOV19. Moreover, PE was associated with a reduced increase of perceived negative effects during the course of the pandemic over six months on the dimensions of physical and emotional well-being, cognitive functioning, social contacts, expectations for the future, and on the PICOV19 total score.Limitations result mainly from the fact that our study design was not developed to measure effects of the COVID-19 pandemic. As a consequence we do not have real baseline measures for the effects of the pandemic. In addition, the fact that the study sample includes only participants who were eligible for the enrollment in the GBV program, limits the representability of the results with regard to the population of patients with SMI.Independent of their SARS-CoV II infection status patients with SMI had a high risk of experiencing negative consequences of the COVID-19 pandemic on their daily lives. Perception of negative consequences increased with severity of illness and decreased with the level of perceived empowerment (PE). Promotion of PE should be considered an important component of mental health care in this target group ,67. This paper was transferred from another journal. 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