Importantly, about 20% of PRNT+ individuals lost their neutralizing antibodies within five months. Here, we show that neutralizing antibodies are detectable in only one third of those with a positive immunoassay result, and wane relatively quickly.To estimate the seroprevalence and temporal course of SARS-CoV-2 neutralizing antibodies, we embedded a multi-tiered seroprevalence survey within an ongoing community-based cohort study in Bonn, Germany. We first assessed anti-SARS-CoV-2 immunoglobulin G levels with an immunoassay, followed by confirmatory testing of borderline and positive test results with a recombinant spike-based immunofluorescence assay and a plaque reduction neutralization test (PRNT). Those with a borderline or positive immunoassay result were retested after 4 to 5 months. At baseline, 4771 persons participated (88% response rate). Between April 24 Population-based studies of SARS-CoV-2 seroprevalence are needed to understand levels of immunity and antibody dynamics. Here, the authors show that the seroprevalence in Bonn, Germany was low (<1%) following the first epidemic wave, and that neutralising antibodies waned within a few months. Even after the recent development of highly effective vaccines, accurate estimates of SARS-CoV-2 seroprevalence patterns in the general population remain essential for containing the still raging pandemic as logistic challenges of manufacturing, delivery and deployment, as well as preconceptions against vaccination, are expected to severely delay their timely and widespread administration5. Moreover, still much remains unknown about the efficacy of currently available vaccines against emerging SARS-CoV-2 strains6. Seroprevalence, correlates and temporal dynamics of SARS-CoV-2 neutralizing antibodies are crucial for gauging population immunity, but have hardly been investigated in seroepidemiological studies to date9. Population studies are the only way to gain knowledge about the prevalence of asymptomatic and mildly symptomatic cases, as well as the potency and sustainability of their acquired immune response, both of which are of paramount importance from a public health perspective, because such individuals often elude the classical symptom-based infection chain tracking, but yet play a key role in the further spreading and sustainment of the current global outbreak10. Moreover, seroprevalence studies provide important benchmarks for tracking the evolution of the pandemic by enabling incidence estimates at population-level11.As of January 2020. Many of these estimates may have been biased17, due to inadequate sampling methods, poor antibody test performance, non-random sampling , a non-representative sampling setting , as well as small sample sizes17. Especially, studies that compare seroprevalence estimates based on multiple sampling approaches covering the same geographical region and timeframe, while using standardized serological assays, are urgently needed as these could enable a better estimation of the magnitude of bias engendered by using convenience sampling methods, that are currently the main source of seroprevalence estimates for most parts of the world21. In Germany, while several seroprevalence studies are still ongoing, findings of only a few serosurveys have been published. Only three of these were population-based studies24, while the remaining assessments targeted industrial workers, health-care providers, mothers, students/teachers, or blood donors18. COVID-19-related morbidity and mortality rates have been relatively low in Germany compared to other (European) countries26, yet the true exposure state of the population could be much higher given the unknown proportion of SARS-CoV-2 infections with mild or asymptomatic course15.Many population-based SARS-CoV-2 serosurveillance studies have already been performed around the globe with widely varying seroprevalence estimates27. The current gold standard for SARS-CoV-2 serology are neutralization assays27. The presence of antibodies that can neutralize the virus is highly specific for having sustained an infection, and is also thought to constitute a major component of the acquired immunity to the virus28. However, neutralization assays are highly laborious, can only be performed in specialized  laboratories, and hitherto have hardly been used in serosurveys. Thus, currently little is known about the determinants, correlates and temporal evolution of SARS-CoV-2 neutralizing antibodies at population-level.An important challenge for accurate assessment of SARS-CoV-2 seroprevalence, especially in regions with a relatively low infection rate, is insufficient specificity of the serological tests. Widely used (point-of-care) lateral flow and quantitative ELISAs lead to a relatively large number of false positives due to cross-reactivity with other (endemic) coronavirusesWe aimed to (1) accurately estimate the prevalence of SARS-CoV-2 seropositivity in a region with a relatively low infection rate, using a multitiered serological testing strategy including highly specific neutralization assays, and (2) investigate the correlates and temporal dynamics of neutralizing antibodies against SARS-CoV-2, with a particular focus on the characteristics of infected but asymptomatic or mildly/moderately symptomatic individuals. By embedding a large-scale seroepidemiological study within the pre-existing framework of an ongoing prospective community-based cohort study, we intended to prevent self-referral bias, ensure long-term follow-up of the participants (including future seroconversion), and facilitate the investigation of genetic, health, and lifestyle determinants of susceptibility and resilience to SARS-CoV-2 infection. In this report, we present the findings of the first serosurvey including follow-up of all individuals with a neutralizing antibody response against SARS-CoV-2.Cohort characteristics and the serosurvey results of Group I are displayed in Table The prevalence estimate based on ELISA results only, an approach that prioritizes sensitivity and thereby provides an estimate of the upper bound of the seroprevalence, was 0.97% : 0.72–1.30). When only treating those participants as cases who had tested positive on all three tests , see Fig. The seroprevalence estimates were neither significantly associated with age (odds ratio (OR) 1.00 (95% CI: 0.98–1.02) for ELISA, and OR 0.98 (95% CI: 0.94–1.03) for all three tests) nor sex  for ELISA, and 0.56 (95% CI: 0.23–1.40) for all three tests).p < 0.018; Fig. The 17 individuals with neutralizing antibodies came from 15 different households, including two households with two cases each and two households with one participant with and one without neutralizing antibodies. Only one individual had suffered from severe COVID-19 requiring hospitalization and intensive care treatment. The other 16 individuals had not required hospital care and were therefore assumed to have had asymptomatic or mild to moderate infection: All of them reported having experienced at least one symptom since January 1st 2020  ratio: 2.62, 95% CI: 1.81–3.43) Fig. . In addiP = 0.05). Neither age  nor sex  differentiated between the two groups. Those with neutralizing antibodies reported having experienced more symptoms , whereas other factors—including education, body mass index, comorbidity, alcohol consumption, smoking, and vaccination against seasonal influenza, pneumococcus, or tuberculosis—did not differentiate between the two groups . The odds of neutralizing antibody seropositivity significantly increased with loss of appetite, muscle weakness, chills or hot flashes, and a reduced sense of taste . However, as compared to Group I, Group II individuals were slightly less likely to report symptoms . Importantly, however, the proportion of people who reported having a household member with a confirmed SARS-CoV-2 infection was substantially higher in Group II compared to Group I . In addition, a higher proportion of people in Group II, as compared to Group I, reported having been previously tested positive for a SARS-CoV-2 infection .A summary of the sample characteristics and test results of this group is presented in Supplementary Table All individuals from both Group I and II, who had a borderline ELISA result at baseline were invited for a return visit within about 8 weeks of the first blood withdrawal. 30 of the 39 invited individuals returned for follow-up testing after a median of 28 days (range 20–41 days). At follow-up the IgG ratio had increased beyond 1.1 in seven of these individuals; however, neutralizing antibodies could not be detected in any of these participants at the follow-up visit, not even in the individual in whom the presence of neutralizing antibodies was confirmed at the baseline visit  at baseline. Of these individuals, 83 came for a follow-up blood withdrawal (response rate ≈ 90%), including all 22 individuals in whom the presence of neutralizing antibodies had previously been confirmed. The blood withdrawals were performed after a median of 120 days from the baseline visit (range 89–144 days).50 titer levels per day = 0.99, 95% CI: 0.98–0.99), with neutralizing antibodies becoming undetectable in 4 out of 22 individuals who were PRNT+ at baseline . Similarly, higher titers of neutralizing antibodies at baseline were associated with a lower probability of becoming neutralizing antibody negative after follow-up (OR for time (in days) × PRNT50 titers interaction = 0.18, 95% CI: 0.18–0.19, P << 0.001). There was also a group of four individuals, with PRNT50 titers in the >1:80 range at both visits, in whom the titers of neutralizing antibodies robustly increased during follow-up as evidence by higher PRNT90 at the follow-up as compared to the baseline visit  only about one third of the individuals who tested positive on a widely used quantitative immunoassay had detectable levels of serum neutralizing antibodies; (2) both the magnitude of the antibody response, as reflected by the IgG ratio, the total number of symptoms experienced, as well as the presence of particular symptoms were associated with the presence of neutralizing antibodies in those with a positive immunoassay test result; (3) in those with a borderline immunoassay result the presence of neutralizing antibodies was extremely rare, and—in the only confirmed case—transient, (4) the titers of neutralizing antibodies wane relatively quickly, decreasing below detection limit in a sizeable proportion (about 20%) within a few months, with the probability of neutralizing antibody loss being inversely related to the magnitude of the IgG response, and (5) self-referral bias can lead to substantial overestimation of seroprevalence.We present the findings of the largest population-based SARS-CoV-2 seroepidemiological cohort study to date in Germany. We conducted a study between April 24th, there were a total of 759 confirmed SARS-CoV-2 infections (including three COVID-19 related deaths) in Bonn, a city with about 330,000 inhabitants, yielding a prevalence of 0.23%29. Our seroprevalence estimates are 1.6–4.2 times higher . The study sample did not include people younger than 30 years old and is, therefore, not representative of the entire Bonn population. Nevertheless, our findings suggest that a considerable number of individuals who had been infected went undetected by the local health regulatory agencies, most likely because of subclinical infection or development of mild symptoms only. Our findings also confirm that limited exposure of the local population to SARS-CoV-2 most likely accounts for the relatively low rates of regional COVID-19-related hospitalizations and mortality at the time, supporting the efficacy of early implementation of social distancing and confinement measures in Germany26. Our seroprevalence estimates are lower than the three other German community-based serosurveys, which were conducted during the first wave of the pandemic24. However, these previous serosurveys were conducted in communities following super-spreading events, and are unlikely to reflect the state of other regions in Germany with relatively low COVID-19 burden24.As of June 3027. Second, this group may also include individuals who were infected with SARS-CoV-2, but who either did not develop neutralizing antibodies or lost them in the period following infection. Indeed, we could not detect neutralizing antibodies in 6 out of 15 people who reported to have had a SARS-CoV-2 infection in the past. In addition, we found that neutralizing antibody titers decreased below detection in about 20% of seropositive individuals within just 5 months of follow-up. Although another recent study found a more sustained neutralizing antibody response, the study used a microneutralization assay and the cohort included a substantial group of people who were referred for screening based on suspected COVID-19, and thus likely had more severe disease, not representing an unbiased population-based sample30. Conversely, our findings further extend other recent reports indicating that neutralizing antibodies may not develop in asymptomatic or only mildly symptomatic individuals and, especially in this group, may wane relatively quickly in the period following infection28. Although neutralizing antibodies are thought to be a major component of adaptive immunity and their levels also strongly correlate with the number of SARS-CoV-2 specific T-cells31, a decline of neutralizing antibody levels does not necessarily imply absence of persisting immune memory32. Indeed, SARS-CoV-2 specific T-cells recognizing peptides derived from the spike, nucleoprotein, and matrix components of the virus have also been found in convalescent plasma following mild COVID-19 and could potentially confer a longer lasting immunity33. Similarly, despite decreasing antibody levels after about three weeks post-symptom onset, a recent study found that the number of long-lived memory B cells in blood samples obtained from 25 convalescent COVID-19 patients continued to rise until about 5 months34. Though there is still much to be learned about which components of the immune response provide protection against both initial infection and reinfection, recent evidence from SARS-CoV-2 vaccine trials support the notion that the presence and magnitude of neutralizing antibodies can be regarded as a valid marker of a protective immune response37. Therefore, the possibility cannot be excluded that even after infection a large proportion of individuals in the general population, especially those with asymptomatic or mild infections, may become susceptible again to SARS-CoV-2 infection.Neutralizing antibodies were detected in only about one third of the participants who tested positive on a widely used immunoassay. At least two explanations may account for this finding. First, the individuals who tested positive on the immunoassay but not on the confirmatory tests, may be false positives, e.g., due to cross-reactivity with antibodies against other coronaviruses. Based on a specificity of 99.6% for the ELISA that we used and assuming a zero prevalence, we would have expected 19 false positivesAmong persons with a positive immunoassay result, the magnitude of the IgG response, the number of previously experienced symptoms, as well as the prior occurrence of particular symptoms—including loss of appetite, muscle weakness, chills or hot flushes and reduced taste—were strongly associated with the probability of having neutralizing antibodies. In addition, titers of neutralizing antibody were also strongly associated with the magnitude of the IgG response, as well as some clinical features like the number of co-morbidities and BMI. These findings thus suggest that predictive models could be developed, based on a combination of clinical characteristics and immunoassay-based antibody levels to estimate both the probability and the magnitude of the neutralizing antibody response. Testing for neutralizing antibodies is currently very labor intensive and can only be reliably performed in specialized laboratories. Good prediction models could be useful to better estimate the actual population immunity level in regions without access to such advanced testing facilities.38. In order to estimate the magnitude of this effect, we also sampled a group of spontaneous volunteers from the same region who were not part of the original Rhineland Study cohort, but who expressed interest in the serosurvey. After formal invitation of these individuals, the response rate was almost 30% lower compared to the original cohort of participants, whereas the seroprevalence estimates were two to four-fold higher . It appeared that the main reasons for self-selection were not so much the presence of symptoms, but a previously confirmed SARS-CoV-2 infection or the presence of a close contact with a previous SARS-CoV-2 infection. These findings thus illustrate the profound impact of selection-bias on seroprevalence estimates—likely a major source for the large heterogeneity of the findings of many previous serosurveys—and thereby underscore the critical importance of cohort-based analyses that allow for accurate quantification of response rate and reasons for (non-)response.Self-referral or volunteer bias could inflate seroprevalence estimates40. Nevertheless, given the low  seroprevalence, it is highly unlikely that the population seroprevalence in this region at the time would have materially differed from our estimates.Our study has both strengths and limitations. By implementing this serosurvey in an ongoing community-based prospective cohort study, we were able to quickly reach and mobilize a large group of participants and achieve a very high response rate, thereby minimizing the risk of selection bias. Indeed, to the best of our knowledge, our serosurvey is the only available study in which the magnitude of self-selection bias has been specifically addressed with respect to SARS-CoV-2 seroprevalence. By presenting differences in the seropositivity rates for participants from Group I (low risk of self-selection) and Group II (high risk of self-selection), who otherwise originated from the same pre-defined geographical region, our study can be used to illustrate and warn against the substantial influence of self-referral/self-selection bias in inflating seroprevalence estimates. We also present one of the very few follow-up studies targeting both the correlates and temporal evolution of the neutralizing antibody response at population-level. The limitations of our study include that it was restricted to adults ≥30 years, and the fact that we did not assess SARS-CoV-2 specific T-cell and memory B cell responses, other critical components of acquired immunityIn conclusion, neutralizing antibodies to SARS-CoV-2 were detectable in only one third of those with a positive immunoassay result and waned relatively rapidly within a few months. These findings not only indicate that almost the entire population in this region was susceptible to SARS-CoV-2 infection at the time, but also suggest that without vaccination sustained population immunity to SARS-CoV-2 is difficult to achieve, warranting continued vigilance and implementation of countermeasures to curb the further spread of the infection by health authorities.41. The study started in 2016 and emphasizes deep phenotyping. Because of the imposition of local lockdown measures, regular study visits were paused on March 18th, 2020.This serosurvey was based on the Rhineland Study, an ongoing community-based cohort study in Bonn, Germany. All inhabitants aged 30 years and above of two geographically defined areas are invited to participate in the Rhineland Study. The sole exclusion criterion is insufficient command of the German language to provide informed consent. Persons living in the recruitment areas are predominantly German from Caucasian descent. The Rhineland Study’s overarching aims are to investigate the etiology and prediction of age-related (neurodegenerative) diseases, and to assess normal and pathological (brain) structure and function over the adult life courseth, 2020 (N = 5427). Their participation in the study was therefore unrelated to attitude to or experience with SARS-CoV-2. Group II consisted of individuals who were eligible for but had not yet participated in the Rhineland Study. They actively approached us to indicate their willingness to participate in the serosurvey (N = 597), which we allowed for those who agreed to become prospective participants in the Rhineland Study. Participation in this group was thus motivated by the prospect of being tested.This serosurvey was conducted in two groups. Group I consisted of all living participants who had been enrolled in the Rhineland Study until March 18Approval to undertake the Rhineland Study was obtained from the ethics committee of the University of Bonn, Medical Faculty (reference ID: 338/15). The Rhineland Study is carried out in accordance with the recommendations of the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) standards (ICH-GCP) after obtainment of written informed consent from all participants in accordance with the Declaration of Helsinki. No separate ethical approval for this serosurvey was required given its embedding in the Rhineland Study, the ethical mandate of which already covered follow-up measurements, including collection of serial bio-samples.th through June 30th, 4771 (88%) of the invited participants from Group I and 360 (60%) of the invited participants from Group II, visited one of the study centers for a blood withdrawal. Reasons for non-response included death, undeliverable invitations, and refusal due to a perceived high burden or risk of infection due to old age, immobility, or co-morbidity.All Group I participants were informed about the serosurvey through email, postal letter and/or phone, whereas, as stated above, Group II individuals actively approached us. All invitees were requested to use a purpose-designed online platform to make an appointment at one of the two local study centers, except when they were suffering from symptoms of an acute infection , in which case they were recommended to visit a doctor. From April 24g, stored directly at +2 to +8 °C thereafter, and sent to the diagnostic lab via overnight courier within about 1 week of collection. Following blood collection, participants received a paper questionnaire that they were asked to complete at home and return to the study center.Data collection included blood withdrawal and questionnaires. At the study center, blood was collected from an antecubital or dorsal hand vein. 30–90 min after blood withdrawal serum tubes were centrifuged for 15 min at 2000 × 42. Importantly, we re-invited all those individuals with IgG levels ≥0.8 at baseline for repeated follow-up measurements of the IgG levels within 3–6 weeks so as not to miss individuals with a nascent humoral immune response after a recent infection. We performed two additional confirmatory tests in all those individuals whose ELISA assay results were either positive  or borderline . Confirmatory tests consisted of an in-house recombinant immunofluorescence test and a PRNT to specifically check for the presence of neutralizing antibodies against SARS-CoV-2 as we described recently44. Neutralizing antibody titers were measured as the concentration of serum to reduce the number of plaques by either 50 or 90%  and categorized as <1:20 , 1:20, 1:40, 1:80 or >1:80. Especially in regions where seroprevalence is expected to be low, minimizing the number of false positives is crucial. Therefore, we tested the specificity of our three-tiered testing approach, using 100 randomly selected pre-pandemic samples from the same cohort , which were collected between 2016 and 2018 during the months March to September to roughly correspond to the timing of sample collection during the pandemic in our serosurvey. All 100 samples tested negative on the commercial ELISA, the in-house recombinant spike-based immunofluorescence test and PRNT, confirming the extremely high specificity of our three-tiered testing approach  using a three-tiered approach. First, the levels of IgG antibodies against SARS-CoV-2 were measured using a commercially available ELISA . According to the manufacture’s product sheet, applying a cut-off of >1.1 for defining seropositivity results in an estimated sensitivity of 94.4% (at >10 days of infection) and specificity of 99.6%. Our independent in-house validation experiments of this assay using serum samples from 119 plasma donors after convalescence from mild to moderate COVID-19 (as documented by positive swab nucleic acid testing), as well as 110 healthy subjects , were in line with the manufacturer’s reported values yielding a sensitivity of 86.8% and a specificity of 100%45, particularly the Lifelines study;46https://www.covid19hg.org), to facilitate future data harmonization, sharing, and collaboration).Data on physical and mental health were collected through an extensive questionnaire addressing current demographic, living and socioeconomic conditions, co-morbidities, medication and substance use, as well as COVID-19 related symptoms. The questions were selected taking account of other ongoing and developing COVID-19 related studies , until the time of blood withdrawal and seropositivity. GEE models with a cumulative logistic link function and an independent covariance structure to account for repeated intra-individual follow-up measurement were used to assess the temporal dynamics and correlates of the neutralizing antibody response47. All GEE confidence intervals were based on the robust Huber-White sandwich variance estimator. In case of subgroups with zero counts, Fisher’s exact test was used instead for intergroup comparisons. All analyses were performed in R (base version 3.6.1). The following R packages were used for the statistical analyses: geepack (version 1.3-1), multgee (version 1.7.0) and stats (version 3.6.3). A two-tailed P-value of <0.05 was considered statistically significant.Descriptive statistics are presented as means and 95% CIs for continuous variables or numbers and percentages for categorical variables. Generalized estimating equations (GEE) with an independent covariance structure within household units were used to account for potential correlations between members of the same household. We used GEE with a logistic link function to estimate seroprevalence. We also applied GEE with either a logistic or Gaussian link function to assess which factors were associated with seropositivity or IgG ratio, respectively, while adjusting for potential confounders. We specifically assessed whether age, sex, education (as a measure of socioeconomic status), pre-existing medical conditions, vaccination, BMI, smoking, or alcohol consumption were associated with these outcomes. In addition, we assessed the relation between the number of different symptoms experienced since January 1Further information on research design is available in the Supplementary InformationPeer Review FileReporting Summary


Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases (IBDs). Immunosuppressive medication is the main therapeutic approach to reducing inflammation of the gastrointestinal tract. Immunocompromised patients are more vulnerable to severe courses of illness after infection with common pathogens. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen of the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 leads to acute respiratory distress syndrome (ARDS) following severe pulmonal damage in a significant number of cases. The worldwide circulation of SARS-CoV-2 has led to major concerns about the management of IBD patients during the pandemic, as these patients are expected to be at greater risk of complications because of their underlying altered immunological condition and immunosuppressive therapies. Vaccination against SARS-CoV-2 is considered the main approach in containing the pandemic. Today, several vaccines have been shown to be highly effective in the prevention of SARS-CoV-2 infection and severe disease course in subjects without underlying conditions in respective registration studies. Patients with underlying conditions such as IBD and/or immunosuppressive therapies were not included in the registration studies, so little is known about effectiveness and safety of SARS-CoV-2 vaccination in immunocompromised IBD patients. This review provides an overview of the recent knowledge about vaccine response in IBD patients after vaccination against SARS-CoV-2. Crohn’s disease (CD) and ulcerative colitis (UC) are chronic remittent inflammatory bowel diseases (IBDs). Immunosuppressive medication is the predominant therapeutic approach for reducing inflammation of the gastrointestinal tract ,2. ImmunThe severe acute respiratory syndrome coronovirus-2 (SARS-CoV-2) is the pathogen of the coronavirus disease 2019 (COVID-19) pandemic . In a siUntil recently, only a few therapies were shown to be effective in combatting COVID-19. Glucocorticoid dexamethasone and the interleukin-6 antagonist tocilizumab were shown to significantly reduce hyperinflammation and mortality in severely and critically ill COVID-19 patients ,11. DespVaccination against SARS-CoV-2 is considered the most suitable approach for containing the pandemic. Several vaccines have been approved for application in humans and have been shown to be highly effective in the prevention of SARS-CoV-2 infection and severe disease course in subjects without underlying conditions in respective registration studies. Patients with underlying conditions such as IBD, or those undertaking immunosuppressive therapies, were not included in the registration studies. As a result, little is known about the effectiveness, side-effects, and safety of SARS-CoV-2 vaccination in IBD patients, especially in the case of required immunosuppressive therapies. Recent studies revealed attenuated immune responses to SARS-CoV-2 infection in patients treated with immunomodulating therapies , suggesting an attenuated immune response following vaccination .This review offers an overview about current knowledge regarding vaccine responses in IBD patients after vaccination against SARS-CoV-2.We performed an electronic database search using PubMed and searched for studies accepted to PubMed during 2020 until 30 August 2021. We conducted the PubMed search using the keywords “IBD”, “inflammatory bowel disease”, “COVID-19”, and “vaccination”. The keywords were combined using the operator “AND”. Three reviewers independently screened the titles of the studies retrieved from the search. Only studies addressing the effectiveness and safety of anti SARS-CoV-2 vaccines in IBD patients were selected for further reading. Of them, only studies investigating humoral and cellular response and safety were included in the review. Selected studies were screened for further available literature regarding safety and humoral/cellular response in IBD patients. To address recommendations of SARS-CoV-2 vaccination in IBD patients, international guideline articles were also included and screened for further literature addressing the above-mentioned criteria. The selected titles from each of the three reviewers were combined and duplicates were removed. The included articles were reviewed for IBD cohort characteristics, IBD medication, humoral responses , and cellular responses in the context of IBD medication and safety data after vaccination.All selected studies revealed data on seroconversion rates with the following anti-SARS CoV-2 spike antibody concentration cut-off values while using different assays: Kennedy et al. ≥15 U/mL; Reuken et al. ≥33.8 BAU/mL and ≥13 AU/mL; Kappelmann et al. ≥1µg/mL; Wong et al. ≥10 sCOVG Index; Podzdyakova et al. ≥50 AU/mL. Reuken et al. and Kennedy et al. presented data after the first vaccination (BNT162b2 and ChAdOx1) and Reuken et al., Pozdnyakova et al., Spencer et al., Wong et al., Kappelmann et al., and Kennedy et al. presented data up to 90 days after second vaccination . To conduct a meta-analysis on seroconversion rates, we extracted complete data of IBD patients  of each study  and calculated the percentage proportion of seroconverted participants.At the time of writing, four SARS-CoV-2 vaccines have been approved in Germany and most European countries. All four vaccines target the SARS-CoV-2 spike protein of the virus, which binds to the ACE receptor on human cells and is essential for the cell entry of the virus. The mRNA-1273  and BNT162b2 (BioNTech/Pfizer) vaccines are both mRNA vaccines. In both cases, the mRNA is packed into lipid nanoparticles, delivering the mRNA into human cells after injection. Cells are then able to synthesize the spike protein, which was shown to be able to induce both neutralizing antibodies and T-cellular immune responses. In phase III trials, both vaccines showed an efficiency above 94% in preventing COVID-19 in the study population, accompanying a good safety profile ,16. The The phase III trials of the above-mentioned vaccines did not include patients using immunosuppressive therapies, which is why little is known about safety and efficiency in these patients. Meanwhile, a rising number of studies found an impaired immune response in patients using immunosuppressive therapies compared to healthy controls, which has even led to the suggestion of applying a third dose of the vaccine to selected patients . While qFirst, we screened the selected literature for data demonstrating seroconversion rates in IBD patients .Next, we conducted a meta-analysis of seroconversion rates as described in the methods section. For meta-analysis of seroconversion rates after first vaccination with the BNT162b2 or ChAdOx1 vaccine, the data of 895 participants were available. Of them, 363 (40.6%) participants seroconverted up to two weeks after vaccination. Data up to 90 days after second vaccination with BNT162b2, ChAdOx1, mRNA-1273, and Ad26.CoV2.S from 676 participants were available. Of them, 652 (96.4%) participants seroconverted after the second vaccination .The effectiveness of vaccination against infection with SARS-CoV-2 has not been examined prospectively, but Khan et al. retrospectively analyzed 14.679 IBD patients in a veteran cohort, of whom at least 7321 received one dose of the vaccine. The overall cohort received a broad spectrum of immunosuppressive therapies . Median age was 68 years and 61.8% had ulcerative colitis. In total, 45.2% received the Pfizer vaccine and 54.8% received the Moderna vaccine. This study found an effectiveness of 80.4% against SARS-CoV-2 infection seven days after two vaccinations compared to the unvaccinated cohort. No differences were found in IBD medication subgroups. Overall mortality was not significantly different in vaccinated and unvaccinated patients, perhaps due to relatively low numbers of infection in both groups .Only minimal data are available regarding the safety of SARS-CoV-2 vaccination in immunocompromised IBD patients. Botwin et al. longitudinally surveyed 246 IBD patients who received at least one dose of a two-dose vaccination series of either the BNT162b2 or the mRNA-1273 vaccine. Adverse events (AE) were documented for eight days following each dose. In total, 80% of patients received multiple IBD medications  and 20% did not receive any immune-compromising therapies at the time of vaccination. Moreover, 57% received BNT162b2 and 42.7% received mRNA-1273, while 67% had Crohn’s disease and 33% ulcerative/indeterminate colitis. The rates of AE after the first and second vaccine doses were comparable to previously reported rates in healthy subjects, and severe AEs were considerably rare. AEs were more common in UC patients than in CD patients (78% vs. 55%). Younger age was identified as a risk factor for increased AE rates, whereas AEs in individuals receiving any immunomodulating therapy at the time of vaccination was less common. This is the largest available study in this field; taken together, these data suggest a safe profile for SARS-CoV-2 mRNA vaccines in IBD patients in relation to immunomodulating therapies during the first eight days following either one or two vaccine doses .Available studies reveal promising data on vaccination effectiveness and safety in immunocompromised IBD patients, showing high seroconversion rates, strong T-cell responses and pronounced protection against SARS-CoV-2 infection despite ongoing immunosuppressive therapies without relevant side effects. While occasional case reports on influenza vaccinations have raised the concern that vaccinations could trigger a flare of the IBD, larger studies on H1N1 vaccinations in IBD have shown no effect on disease activity in vaccinated patients. In a study with >500 IBD patients, Rahier et al. showed that only 3.9% of participants experienced a self-limiting clinical disease flare after influenza vaccine administration , supportWhile a flare up of underlying IBD following vaccination appears to be of minor concern, there is the possibility that patients taking immunosuppressive medication will have a reduced vaccine effectiveness due to impaired immune responses. Some studies highlight the importance of full vaccination, leading to significantly improved immune responses after the second vaccine dose of mRNA and vector vaccines . The datIn comparison, an increasing number of studies on SARS-CoV-2 vaccinations in solid organ transplant (SOT) recipients revealed a significantly attenuated immune response in these patients. For example, Mazzola et al. found a seroconversion rate of only 28.6% 28 days after the second SARS-CoV-2 vaccination with the BNT162b2 vaccine in SOT recipients receiving immunosuppressive therapies with calineurin inhibitors, mycophenolic acid, mTor inhibitors, and steroids . Perry eMany national and international regulatory and advisory boards have published vaccination recommendations aiming at sufficiently protecting patients at increased risk of contracting COVID-19 and experiencing a complicated or even fatal course of the disease. As, to date, there are no prospective studies reporting the effect of any SARS-CoV-2 vaccine specifically in patients with IBD, only few expert guidelines on SARS-CoV-2 vaccinations for IBD patients exist or were published in the early stages of the pandemic. A position statement by the British Society of Gastroenterology Inflammatory Bowel Disease section and IBD Clinical Research Group was issued in the beginning of 2021, at a time in which the British healthcare system was under considerable strain and vaccine availability was limited . MeanwhiGiven the theoretical risk of suboptimal immune responses on the one hand and an apparently higher effectiveness of mRNA-based vaccines, there could be a rationale for a preferred use of these vaccines in IBD patients. Additionally, IBD patients are typically of a younger age and carry an increased risk for venous thromboembolism due to their underlying disease ,41,42. AAlthough active IBD should not be a contraindication to vaccination in general, severe flares which require hospitalization and aggravated immunosuppression might require a postponed vaccine administration. If possible, vaccination should be performed while the patient is under stable therapy with the lowest possible level of immunosuppression. However, reducing immunosuppression just for the purpose of vaccine administration is not advisable, while waiting shortly for an already planned steroid taper, e.g., is rational. In any case, a thorough discussion and information of the patient based on individual circumstances is necessary .In our clinical practice, we do not perform serology testing for SARS-CoV-2 before administering vaccination, even in people with suspected or proven prior infection, which is also in line with published recommendations . It has Recently, booster immunizations have been proposed for selected patient cohorts and medical personnel and small studies in solid organ transplant recipients have suggested the application of a third dose of the BNT162b2 vaccine to enhance antiviral immunity . At presOur own meta-analysis of six available studies revealed an outstanding effectiveness of vaccination in IBD patients with a seroconversion rate of 96.4% in overall 676 participants up to 90 days after second vaccination. Nonetheless, the low number of available studies investigating the effectiveness and safety of SARS-CoV-2 vaccination in IBD patients and the small study size of these available studies are a relevant limitation in this review. Furthermore, not all studies differentiated in detail the IBD medication subgroups and the used vaccines in reporting the seroconversion rates, so that a meta-analysis on subgroups was not possible. A further limitation regards the influence of antibody concentrations on the effectiveness against severe disease in immunocompromised IBD patients. The available studies reported only in part absolute antibody concentrations; a meta-analysis was not possible due to different units in reporting the antibody concentrations. Larger studies are needed to investigate exact differences of immune responses and safety in IBD subgroups. Furthermore, available studies provide insufficient data regarding the influence of age, length of IBD history, type of IBD (Crohn’s disease vs. ulcerative colitis), and extraintestinal manifestations of vaccine response. However, the current literature points out that vaccinations against SARS-CoV-2 infections are safe and all in all effective in IBD patients and can strongly be recommended.


The Oral versus Intravenous Antibiotics for Bone and Joint Infection (OVIVA) trial determined oral antibiotics administered during the first six weeks of therapy were non-inferior to parenteral antibiotics. There was no difference in the incidence of serious adverse effects. The objective of this study was to evaluate the safety and effectiveness of de-escalating to oral therapy compared to continuing parenteral vancomycin therapy in patients with orthopedic infections in a real-world setting.We conducted a single-center, retrospective cohort study of patients discharged between April 1, 2018 and April 1, 2020 with an orthopedic infection, a prescription for at least four weeks of parenteral vancomycin, and documented follow-up. The primary outcome was incidence of adverse events defined as provider documentation of the event and changes to therapy. The secondary outcome was incidence of 6-month treatment failure defined as repeat surgical intervention or therapy escalation. One hundred fifty-seven patients were included. Twenty-nine (18.5%) patients were de-escalated to oral therapy. Three (10%) patients in the oral therapy group had an adverse event compared to 35 (27%) in the vancomycin group (p=0.058). Of the 35 patients with an adverse event in the vancomycin group, eight were due to parenteral access-related complications. Treatment failure occurred in three (10%) patients in the oral therapy group compared to 27 (21%) patients in the vancomycin group (p=0.29). Three (10%) patients in the oral therapy group had an unplanned readmission compared to 25 (20%) patients in the vancomycin group (p=0.24).Baseline Characteristics, Unplanned Readmission Rates, and Incidence of Adverse Events and 6-Month Treatment FailurePatients de-escalated to oral therapy had fewer adverse events and similar incidences of treatment failure compared to patients maintained on parenteral vancomycin. Switching to oral therapy avoids some adverse events related to parenteral access. Our results in an uncontrolled, real-world setting are consistent with the OVIVA trial. Though limited by sample size, our data indicate switching to oral therapy in patients with an orthopedic infection improves safety outcomes without compromising effectiveness compared to continued parenteral vancomycin therapy.Russell J. Benefield, PharmD, Paratek Pharmaceuticals (Grant/Research Support)


Background: The goal of cardiac evaluation of patients awaiting orthotopic liver transplantation (OLT) is to identify the patients at risk for cardiovascular events (CVEs) in the peri- and postoperative periods by opportunistic evaluation of coronary artery calcium (CAC) in non-gated abdominal computed tomographs (CT). Methods: We hypothesized that in patients with OLT, a combination of Lee’s revised cardiac index (RCRI) and CAC scoring would improve diagnostic accuracy and prognostic impact compared to non-invasive cardiac testing. Therefore, we retrospectively evaluated 169 patients and compared prediction of CVEs by both methods. Results: Standard workup identified 22 patients with a high risk for CVEs during the transplant period, leading to coronary interventions. Eighteen patients had a CVE after transplant and a CAC score > 0. The combination of CAC and RCRI ≥ 2 had better negative (NPV) and positive predictive values (PPV) for CVEs  than standard non-invasive stress tests . Conclusion: The cutoff value of CAC > 0 by non-gated CTs combined with RCRI ≥ 2 is highly sensitive for identifying patients at risk for CVEs in the OLT population. Cardiovascular disease is the leading cause of non-graft-related death after orthotopic liver transplantation  . As patiThere is no consensus on the preferred screening test to detect CAD in the pre-LT population nor for post-LT cardiac evaluation. The methods of cardiac assessment differ from site to site ,8,17. ThNon-invasive testing for CAD may be performed by dobutamine stress echocardiography (DES) , cardiacThis retrospective cohort study was approved by the local ethics committee . Data were collected from the electronic health records and the liver transplant database at the University Hospital Aachen. Our analyses were conducted with adherence to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines .Two hundred and seventy patients receiving an OLT in our university hospital from October 2010 to January 2018 were screened for study enrollment. Patients met the inclusion criteria if a pre-transplant evaluation included non-ECG-synchronized CT, which included scans covering the heart to a large extent. The follow-up of all patients continued until January 2019 by checking the electronical data recordings of the hospital. Patients who chose not to follow up in our hospital were asked to provide their newest medical records from their treating physician.Overall cardiovascular risk was assessed by Lee’s revised cardiac index (RCRI) . Pre-traThe primary endpoint of this study was the occurrence of cardiovascular events (CVE) following OLT. CVE is defined as acute coronary syndrome, necessity of coronary revascularization or cardiopulmonary resuscitation. Death was not included as cause of death was frequently unclear. Therefore, the aim of this study was to describe the predictive value of CAC scores obtained from non-ECG-synchronized CT for CVE and compare them to RCRI ≥ 2 and pathologic non-invasive stress testing of the heart.The quantitative evaluation of coronary artery calcifications (CAC) was performed using non-ECG-synchronized CT scans. These were non-contrast or contrast-enhanced examinations of the abdomen or liver that were performed as part of the regular pre-OLT work-up ,35.Normally, this protocol consists of a native, arterial, portal venous and a late phase of the venous contrast medium and routinely covers large parts of the heart. When the native examination has been omitted, the venous contrast agent phase or the phase with the biggest heart coverage is preferred for measuring CAC.In case of absence of the native phase and due to vascular attenuation by the contrast medium, the threshold value for identifying calcium was chosen to be two standard deviations above the vascular mean value determined by ROI (Region of Interest) measurement. The standard reconstruction kernel (B30f) and a slice with 5 mm thickness were selected. Two experienced readers quantified, in consensus, the resulting Agatston and volume scores for all coronary vessels and aortic valve leaflets.The differences between groups for parametric data were analyzed by t-test or Mann–Whitney U test and displayed by mean and standard deviation or range (minimum–maximum). Nominal or ordinal scaled data were investigated for significant differences between groups by the chi-square test and reported as absolute and relative occurrence . The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of each test to predict CVE were calculated according to the usual definitions. Furthermore, only the combination of an RCRI ≥ 2 and CAC > 0 was of interest as they require no additional testing. The McNemar test was used to compare the sensitivities, specificities and diagnostic accuracy of the different scores or tests.One hundred and sixty-nine patients met the inclusion criteria of non-ECG-synchronized CT scans including large parts of the heart. During the follow-up period (1797 days (MW), range 1–3268) after OLT, 18/169 (10.7%) patients showed a CVE. Patients with CVE were older and more often male, but they had an equal BMI, labMELD and distribution of underlying cause of liver disease. There were no significant differences in left ventricular function (LVEF) pre-transplant. Patients were more often already diagnosed with hypertension and diabetes before OLT. Their diagnosis of CAD was also reflected by their differences in medication by aspirin, ß-blockers and statins see . Two or p = 0.003). Fifty-eight patients were transplanted without a stress test before OLT. The reasons for missing stress tests are not comprehensible in this retrospective analysis . The distribution of patients having a stress test before OLT showing a CVE post-OLT  is comparable to the number of patients without a stress test having a CVE   passed an ergometric stress test. SPECT demonstrated the highest rate of pathologic results (18%) see .Due to our pre-transplant cardio-workup, 13/111 patients were identified with a suspected obstructive CAD following non-invasive stress testing. Nine patients were scheduled for invasive testing without a prior non-invasive stress test, due to being highly suspicious for obstructive coronary artery disease  as well as due to contraindications for non-invasive stress testing. Twenty-two patients received an invasive coronary angiography (ICA). In summary, invasive testing was more frequent in patients with CVE after transplant. In 3/22 patients receiving an ICA, a percutaneous coronary intervention was performed without repeating the stress test prior to OLT. In the follow-up period, only one of these patients suffered from a non-fatal NSTEMI, but two died due to progressing LV-insufficiency combined with ARDS and cerebral abscesses, respectively.n = 114, 67.5%) and those patients with an Agatston score > 0 . More patients without CVE had CAC = 0 (p < 0.001), while 15/18 with CVE post-OLT demonstrated a positive non-invasive stress test or CAC > 0 . The highest sensitivity to predict CVE post-transplant was given for a CAC > 0 (77.8%). A positive stress test showed the highest specificity to identify patients at risk for CVE post-OLT. Although, the PPV for a pathologic stress test was only 54.5% in our setting. On the contrary, the combination of two or more RCRI and CAC > 0 showed a PPV of 81.6% for CVE post-OLT. The negative predictive values for stress testing (NPV = 92.0%) were comparable to a CAC = 0 and RCRI ≥ 2 (NPV = 96.5%).We discriminated between patients without an Agatston score at all (CAC = 0, In this single-center retrospective analysis of 169 OLT recipients, we found a 10.7% incidence of CVE post-OLT. This occurrence is comparable to published data . We demoThere are two different etiologies for perioperative myocardial infarction: on demand myocardial ischemia and coronary plaque rupture . Non-invIn OLT patients, the diagnostic accuracy for obstructive coronary artery disease by non-invasive stress testing, as well as of invasive cardiac diagnostic by ICA, is discussed. In a comprehensive systematic review, Konerman et al. reported the striking variability regarding sensitivity for cardiovascular events by different cardiac imaging modalities pre-OLT . DSE migThe 2019 guidelines of the European Society of Cardiologists implemented CAC scoring to determine the clinical likelihood of obstructive CAD in pre-operative work-up for major non-cardiac surgery . CAD is Joshi et al. as well as Blaha et al. described comparable findings that a CAC = 0 has a high 10-year diagnostic screening role ,47. As fOur results suggest that CAC scoring and evaluation of RCRI may reduce the number of non-invasive stress tests and ICAs. Following our results published by Mechelink et al., echocardiography at rest with strain analysis in combination with CAC scoring as well as RCRI will even help to improve the identification of patients at risk .All of the 169 OLT patients reported in this study were treated in the same center under standardized procedures pre-transplant, intraoperatively and post-transplant ,50. TherDetermining the RCRI of a patient and CAC = 0 on routine non-gated CT will help to better identify patients with CAD at risk for a CVE after OLT. The high negative predictive value of Agatston = 0 combined with RCRI ≥ 2 will narrow down the number of patients who have to receive a full cardiac workup before OLT. This concept is particularly practical for the evaluation of highly compromised patients, for example in the intensive ward pre-transplant. Identifying patients at risk for CVE during and after OLT will enable a better organ-to-recipient match regarding the increasing number of ECD organs as well as thorough post-transplant monitoring of these patients.


In this study, weinvestigated the feasibility of using HA-TG in a collagen scaffold to treatchondral lesions in an ovine model, to evaluate cartilage regeneration in amechanically and biologically challenging joint environment, and theinfluence of the surgical procedure on the repair process.Hyaluronic acid–transglutaminase (HA-TG) is an enzymatically crosslinkableadhesive hydrogel with chondrogenic properties demonstrated Chondral defects of 6-mm diameter were created in the stifle joint ofskeletally mature sheep. In a 3-month study, 6 defects were treated withHA-TG in a collagen scaffold to test the stability and biocompatibility ofthe defect filling. In a 6-month study, 6 sheep had 12 defects treated withHA-TG and collagen and 2 sheep had 4 untreated defects. Histologicallyobserved quality of repair tissue and adjacent cartilage wassemiquantitatively assessed.P < 0.05).HA-TG adhered to the native tissue and did not cause any detectable negativereaction in the surrounding tissue. HA-TG in a collagen scaffold supportedinfiltration and chondrogenic differentiation of mesenchymal cells, whichmigrated from the subchondral bone through the calcified cartilage layer.Additionally, HA-TG and collagen treatment led to better adjacent cartilagepreservation compared with empty defects (in situcartilage regeneration and preserves the surrounding cartilage. Thisproof-of-concept study shows the potential of this approach, which should befurther considered in the treatment of cartilage lesions using a single-stepprocedure.This study demonstrates that the adhesive HA-TG hydrogel in a collagenscaffold shows good biocompatibility, supports  If left untreated, cartilage lesions often lead to joint degeneration andeventually to the development of posttraumatic osteoarthritis. About 60% of patients undergoing knee arthroscopic surgery and up to 69% ofadults older than 50 years show signs of cartilage anomalies in their knees. The limited capability of cartilage to heal has driven the development oftissue engineering strategies such as microfracture, autologous chondrocyteimplantation (ACI), and matrix-assisted autologous chondrocyte implantation(MACI).5However, these techniques are often unavailable due to their high costs and theirlong-term outcome is variable or unknown. Furthermore, they present major limitations, which include formation ofmechanically inferior tissue like fibrocartilage,7 lack of integration of thegrafts, the requirement of multiple surgeries and high donor-to-donor variability. Cell-free approaches, using smart biomaterials able to recruit chondrogeniccells and support their differentiation, hold great promises for the development ofsingle step cartilage repair procedures and have been investigated in preclinical and clinical trials. However, these in situ regeneration techniques most oftenuse a combination of a biomaterial with microfracture. Drilling through thesubchondral bone causes bleeding in the defect and thereby allows mesenchymal cellmigration and initiation of repair. Nevertheless, the nature of the cartilage repair tissue is fibrocartilaginousand microfractures have been shown to lead to subchondral cyst formation. Alterations of the subchondral bone have additionally been shown to impaircartilage repair by several mechanisms, such as upward migration of the subchondralbone into the repair site, formation of intralesional osteophytes and subchondralbone cysts as well as changes of the osseous microarchitecture. Further research isneeded to understand the mechanism of action and the efficacy of these cell-free,non-microfracture-associated approaches.Articular cartilage has a limited ability to self-repair after injuries. This ispartly due to its avascular nature that prevents progenitor cells in blood tomigrate to the site of the lesion and the limited number of resident cells. HA-TG is able to direct proliferation and chondrogenic differentiation ofhuman cells from several origins: fetal chondroprogenitor cells (hCCs), infant chondrocytes from polydactyly, and adult auricular chondrocytes. Given its fast gelation kinetics and high adhesive properties to cartilage,we proposed HA-TG as a cell carrier for injectable, cartilage engineeringapplications. Subcutaneous implantation in an ectopic mouse model showed that HA-TGwas not permissive to vascularization, promoted chondrogenesis with encapsulatedcells and led to the formation of stable cartilage grafts. It was unknown, though, whether this biomaterial would support cell migrationand resist the mechanically challenging joint environment.We have previously introduced an adhesive and chondro-inductive hyaluronicacid–derived hydrogel, namely hyaluronic acid–transglutaminase (HA-TG).18 Nevertheless, choosing the most appropriate animal model forthe translation of cartilage engineering application remains a challenge.20 The rabbitmodel is easy to handle and allows chondral defect creation, but spontaneousregeneration has been reported due to increased chondrocyte metabolic activity andhigher cell density in cartilage tissue. The ovine stifle joint model has been used to investigate a range oforthopedic conditions, although the experimental setup varies. While spontaneous healing of smallchondral defects has been shown to occur in fetal lamb, critical size chondral defects of 6 mm diameter in skeletally mature sheep donot fully heal and rather lead to the formation of a scar tissue.23Preclinical studies are a key requirement for the clinical translation of newmedicinal products.in situ cartilage engineering applications in a clinicallyrelevant, large animal model. For this reason, we chose full thickness, chondraldefects in the stifle joint of skeletally mature sheep as a model. The defect modelwas first refined and the biocompatibility of HA-TG in a collagen scaffold(Optimaix) assessed in a short-term (3 months) study. Then, the potential of thiscombination of HA-TG gel and collagen scaffold to support cartilage regeneration andprevent adjacent cartilage breakdown was evaluated in comparison with empty defectsin a 6-month study.The aim of this study was to evaluate HA-TG as a biomaterial for cell-free,HA-TG: HA-TG hydrogel precursors, TG/Gln and TG/Lys, weresynthetized by substituting carboxylic acid moieties of hyaluronan chains with reactive glutamine residue(NQEQVSPL-ERCG) and reactive lysine residues (FKGG-ERCG) respectively aspreviously described.14 HA-TG precursors were solubilized at 2% (w/v) in sterilefiltered Tris buffered glucose solution . The crosslinking was initiated by addingthrombin (Baxter) and factor XIII  to a finalconcentration of 12.5 U/mL and 10 U/mL, respectively.Optimaix-3D (1.5 mm in height) is an open porous porcine collagen I/III sponge(containing <30% w/w elastin) produced by a zero-length crosslinkingprocedure using EDC/NHS chemistry. Optimaix scaffolds were punched into6mm-diameter cylinders and placed in the defect prior to addition of HA-TGhydrogels in order to improve the stability of the HA-TG gel.in vivo experiments were conductedat the Musculoskeletal Research Unit according to Swiss laws for animal welfareand approved by the local governmental authorities .Female, skeletally mature (2-3 years old) healthy Maedi-Visna negative SwissAlpine sheep were used for the experiments from the Musculoskeletal ResearchUnit’s own herd, after being acclimatized for 7 days. Three sheep were randomlychosen by hand from the herd for the 3-months survival group and 8 sheep for the6-months survival group. The The sheep were sedated by intramuscular injection of 0.1 mg/kg xylazine and 0.01mg/kg buprenorphine. Anesthesia was then induced intravenously via a jugularcatheter with 0.1 mg/kg midazolam, 3 mg/kg ketamine, and 0.4 to 0.9 mg/kgpropofol. Following laryngeal desensitization with lidocaine spray, the tracheawas intubated. Anesthesia was maintained with an intravenous constant-rateinfusion of 1 mg/kg/h propofol in combination with 1% to 3% isoflurane inoxygen. Epidural anesthesia was applied with 0.1 mg/kg morphine diluted insterile 0.9% NaCl to a total volume of 2 mL. Intravenous penicillin  and gentamycin  were administered on the day of surgery as preoperative antibioticprophylaxis and for 4 days thereafter. A booster for tetanus  was administered subcutaneous on the day of surgery.Regarding analgesia, carprofen (4 mg/kg) was administered intravenously on theday of surgery and for 4 days thereafter. Buprenorphine (0.01 mg/kg) was applied3 times after surgery, every 4 to 6 hours.Supplemental Figure 1). Full thickness cartilage defects (6 mmin diameter) were created in the weightbearing area in the medial and lateralcondyles of the distal femur of one hind limb, with the other hindlimb leftintact. Operated limbs (left or right) were alternated from one animal to thenext. For the 3-month study, 2 defects per condyle were created. The defect sitewas marked using a biopsy punch. Cartilage was then removed from the defect siteusing a scalpel down to the calcified cartilage layer, and the last step of thedefect debridement was done using a drill burr. For the 6-month study, 1 defectper condyle was created. Defects were created with a device provided by XirosLtd . In all treated defects (6 defects in 3sheep in the 3-month study and 12 defects in 6 sheep in the 6-month study),Optimaix scaffolds were placed in the defect and HA-TG was injected on top.HA-TG was allowed to crosslink for 10 minutes before closing the joint. The 4defects in 2 additional sheep in the 6-month study were left empty as controls embedding, each condyle block was cut in half, following aproximal-distal plane transecting the middle of the defects. One half of eachblock was then used to create one ground section (400-600 µm), starting from themiddle of the defect, and was surface stained with toluidine blue. The secondhalf of the block was trimmed then used to cut 3 thin sections (5 µm), alsostarting from the middle of the defect. The thin sections produced were stainedwith toluidine blue, safranin-O/fast green/hematoxylin and von Kossa/McNeal.Supplemental Table 1), since this score was shown to have a low interobserver variability. Analyzed criteria included bonding of new tissue to adjacent cartilage,interterritorial and pericellular glycosaminoglycan (GAG) staining, cellularityin the defects and cell morphology. For criteria evaluated at both the distaland proximal edges of the defect, an average was calculated in order to computethe total summed score, which was used for statistical analyses . Criteria included the structure of thetissue, its cellularity, the amount of the GAGs present and the integrity of thesubchondral bone. Scoring was done for both the distal and proximal edges of thedefect and the final score was calculated as the sum of the averages of theindividual criteria. The total Little score ranged from 0  to29 . A cyst score was introduced,including criteria of size, isolation from the synovial fluid, the nature of thefilling tissue, the activity of the bone and nonfibrotic tissues . It ranged from 0 (no cyst) to 19 (severecyst with low probability of resorption). The total score, calculated as the sumof the O’Driscoll, Little, and cyst scores, ranged from 0 (best) to 68(worst).Toluidine blue– and safranin-O–stained sections were blind-scored independentlyby 2 individuals using 3 scores to semiquantitatively evaluate repair tissuequality (modified O’Driscoll score), adjacent cartilage state (adapted Littlescore), and subchondral cysts (custom-made score). Modified O’Driscoll score wasused to assess the quality of the repair tissue in the defects  guidelines, as 6 mm full thicknesscartilage defects were expected to be critical size defects and for which, inour previous experience, spontaneous repair does not occurs, thus providing a“no intervention” control allowing to assess the potential effect of a gel andcollagen scaffold treatment. All data from the aforementioned defects/animalswas included in the study analyses. All raw data are kept in the MSRU and ETHZdigital and paper data archives. The GraphPad Prism was used for all statisticaloperations. Comparison of results was carried out by t test  and analysis of variance (ANOVA) using Tukey’s multiple comparisonpost hoc test for significance. The threshold forstatistically significant difference was set at P = 0.05.The 3-month study included The surgical procedure presented no complications. All animals tolerated thesurgery well and showed no persistent lameness or abnormal behavior. There wereno clinical abnormalities noted, beyond those expected after surgery.After 3 months, high variability was observed in the quality of the repairtissue. As evidenced by histological staining, GAG deposition in the defects wasabundant throughout the defect area in the best cases, but only at the borderregions to native cartilage in the worst cases  until the calcified cartilage wasreached.It appeared that the creation of the defect was a cause of variability in thequality of the repair, since the tidemark was violated for some defects . Of note, we observed some cellclusters in GAG-rich regions of the adjacent cartilage, both in treated andempty defects. This corresponded to a score of 4 in the “Cell cloning” sectionof the Little score , which was found in 12 sites (left and/orright side of defects) in treated defects (50%) versus 4 sites in empty defects(50%) .At 6 months, the occurrence of cysts in the subchondral bone was observed on VonKossa–stained sections  with HA-TG, an enzymaticallycrosslinked hyaluronan-based hydrogel, as an acellular tissue engineering approachfor in situ regeneration. Indeed, HA-TG in combination with acollagen I/III sponge (Optimaix) can adhere to the surrounding tissues which isparamount to long-term success of cartilage repair strategies.29 The materialcould also help recruit and retain mesenchymal cells, based on the observation thatdefect fillings were hypercellular  instead of a nontreated control may provide valuable insights forclinical translation, whilst staying in line with 3R principles of animalexperimentation. Further work will be needed to determine the mode of action ofHA-TG + Optimaix.We found histological evidence of mesenchymal-like cells found in the defect filling,which may have possibly migrated from the subchondral bone through the tidemark, intreated defects displaying an intact tidemark. In other words, we could show indefects treated with HA-TG + Optimaix that the presence of an intact subchondralbone provided an environment favorable to mesenchymal cells invasion, whichtheoretically might occur via the CD44 receptor of these cells, Neocartilage is then deposited from the sides into the cartilage defect andprovides an appropriate conduit for further cartilage production and contributes tothe secretion of local trophic factors to induce differentiation of undifferentiatedcells into chondrocytes. Our study implies that cell clustering and proliferation at the edges of thedefects could be important for further matrix deposition and repair within thedefect, which is in contradiction to the accepted view that clusters (as is seen inmany scores) are tied to degeneration and “failed repair” in the context of osteoarthritis. There is likely a spectrum of processes these clusters may be linked to,depending on their surroundings and stage of repair. A mild degradation of thecartilage interface was observed in treated defects at 6 months, which is expecteddue to the mechanical stress resulting from the height variation in the defect area,as well as the lowered chondrocyte viability associated to the surgical preparationof the defects. Yet, HA-TG + Optimaix semiquantitatively better preserved the adjacentcartilage as compared with empty defects, suggesting that the implantedbiomaterials, via the prevention of the nearby cartilage degradation, support tissueregeneration. Indeed, studies have shown that high molecular weight hyaluronan isassociated with anti-inflammatory and immunosuppressive properties that can protectfrom ECM degradation and in turn from chondrocytes apoptosis, which can explain thebeneficial effect of hyaluronan intra-articular injections. It can also behypothesized that HA-TG + Optimaix prevented the mechanical disruption of thesurrounding cartilage deriving from the height gap. Of note, the study design doesnot allow to determine the contribution of the commercial collagen scaffold alone;this group could not be added due to the fact that the collagen scaffold Optimaixcould not stay in the defect without being fixated, as observed with preliminarycadaver tests (data not shown). Additionally, in clinical practice, other collagenscaffolds are usually used in the context of MACI, but not alone.Our study showed that chondrocyte proliferation was taking place in the adjacentcartilage at the edge of the defects, with the presence of many cell clustersespecially in GAG-rich regions. This suggests that the host’s chondrocytes at theedges of the defect also play a vital role in driving the regeneration of thetissue. It was hypothesized that healing of osteochondral defects also happens byneocartilage formation in the cartilage adjacent to the defect. and the tissue regeneration can thus be impaired because of the experimentalsetting rather than the inefficiency of the tested strategy. These facts call for astandardization of defect making, as suggested by Schwarz et al. This standardization is not only important when testing regenerationsolutions in preclinical studies but also when a surgeon is preparing a siteclinically, for the quality of the repair. The status of the subchondral bone belowa cartilage defect correlates with the success rate of clinical regenerativetechniques43 and it is becoming apparent that an intact subchondral bone isnecessary for the success of articular cartilage treatments. Particularly, advancement of the subchondral plate toward the bone has raisedconcern. In our study, we observed such subchondral plate advancement in 3 of the 12treated defects (25%) and in 2 of the 4 defects left empty (50%). The seeminglybeneficial effect of HA-TG + Optimaix with regard to subchondral bone advancementshould be confirmed with a larger study. Of note, the proportion of defectsdisplaying subchondral plate advancement is close to what was reported 12 monthsafter autologous chondrocyte implantation (18%). Although the clinical relevance ofthis advancement is not clear, particular attention should be brought on theprogression of the proportion of defects presenting this feature in longer-termstudies. Given the type of defect filling observed in this study, both a biologicalrole and a biomechanical role (more closely linked to cyst formation) can behighlighted for an intact tidemark.The 6-month study provided a scientific evidence to the commonly acknowledgednecessity to preserve the tidemark while debriding the defect. With higher number ofanimals in the 6-month study, we could highlight a correlation between tidemarkpreservation and quality of cartilage tissue repair. In case of tidemark disruptionduring defect creation, cysts can form as described in the microfracture procedure and to adjacent cartilage degeneration. Optimaix was selected since itimproved HA-TG compressive modulus in vitro without altering HA-TGadhesion to cartilage, which relies on the crosslinking of the HA backbone to theproteins present in the surrounding cartilage, in vitro andin vivo . Despite mechanical reinforcement, the heightof defects filled with HA-TG after 6 months was generally lower than the height ofthe adjacent cartilage. Further work is ongoing to develop a stronger scaffold,whose thickness is higher than that of articular cartilage, in order to promotemechanical stimulation on compression.Von Kossa stainings showed the active remodeling of the subchondral bone, and thepresence of cysts in a third of the treated defects. The uneven heights between thedefect and the surrounding cartilage can lead to cyst formation, as reported in amosaicplasty study,Supplemental Figure 5). The same outcomes described for defectcoverage, defect filling quality, and surrounding cartilage quality were alsoobserved using the alternate statistical analysis, with differences in surroundingcartilage quality detectable in the lateral compartments, but only showing a trendin the medial compartment. Overall, such an alternate analysis would be more robustwith additional datapoints, especially in the untreated group.Finally, in this study, medial and lateral stifle compartments were assumed to actindependently, based on the authors’ historical observations in experimental stiflecartilage defects in sheep, particularly with regard to defect coverage, defectfilling quality and surrounding cartilage quality. Statistical analyses weretherefore conducted by pooling medial and lateral defect data, generating 2 datapoints per animal. It is possible that stifle compartments within the same animalmay not behave independently and therefore would require an alternate statisticalanalysis. An alternate analysis was therefore attempted with the same data setsreported above, but separating datapoints from medial and lateral compartments,thereby using only one datapoint per animal in a comparative cohort (In conclusion, we provide a proof-of-concept of HA-TG biocompatibility and capacityto preserve adjacent cartilage, thus providing a favorable environment for thegeneration of a neocartilage tissue, in a clinically relevant, large animal model.Our study paves the way to a larger preclinical safety study with more sheep andlonger duration before considering entering the phase I clinical trial inhumans.Click here for additional data file.Supplemental material, sj-docx-1-car-10.1177_1947603521989417 for Combination ofa Collagen Scaffold and an Adhesive Hyaluronan-Based Hydrogel for CartilageRegeneration: A Proof of Concept in an Ovine Model by Clara Levinson, EmmaCavalli, Brigitte von Rechenberg, Marcy Zenobi-Wong and Salim E. Darwiche inCARTILAGEClick here for additional data file.Supplemental material, sj-tif-2-car-10.1177_1947603521989417 for Combination of aCollagen Scaffold and an Adhesive Hyaluronan-Based Hydrogel for CartilageRegeneration: A Proof of Concept in an Ovine Model by Clara Levinson, EmmaCavalli, Brigitte von Rechenberg, Marcy Zenobi-Wong and Salim E. Darwiche inCARTILAGEClick here for additional data file.Supplemental material, sj-tif-3-car-10.1177_1947603521989417 for Combination of aCollagen Scaffold and an Adhesive Hyaluronan-Based Hydrogel for CartilageRegeneration: A Proof of Concept in an Ovine Model by Clara Levinson, EmmaCavalli, Brigitte von Rechenberg, Marcy Zenobi-Wong and Salim E. Darwiche inCARTILAGEClick here for additional data file.Supplemental material, sj-tif-4-car-10.1177_1947603521989417 for Combination of aCollagen Scaffold and an Adhesive Hyaluronan-Based Hydrogel for CartilageRegeneration: A Proof of Concept in an Ovine Model by Clara Levinson, EmmaCavalli, Brigitte von Rechenberg, Marcy Zenobi-Wong and Salim E. Darwiche inCARTILAGEClick here for additional data file.Supplemental material, sj-tif-5-car-10.1177_1947603521989417 for Combination of aCollagen Scaffold and an Adhesive Hyaluronan-Based Hydrogel for CartilageRegeneration: A Proof of Concept in an Ovine Model by Clara Levinson, EmmaCavalli, Brigitte von Rechenberg, Marcy Zenobi-Wong and Salim E. Darwiche inCARTILAGEClick here for additional data file.Supplemental material, sj-tiff-6-car-10.1177_1947603521989417 for Combination ofa Collagen Scaffold and an Adhesive Hyaluronan-Based Hydrogel for CartilageRegeneration: A Proof of Concept in an Ovine Model by Clara Levinson, EmmaCavalli, Brigitte von Rechenberg, Marcy Zenobi-Wong and Salim E. Darwiche inCARTILAGE


To assess the magnitude of mental health outcomes and associated factors among psychiatric professionals in mental health services during COVID-19 in China.This cross-sectional, survey-based, region-stratified study collected demographic data and mental health measurements from psychiatric professionals in 34 hospitals between 29 January and 7 February 2020, in China. Hospitals equipped with fever clinics or deployed on wards for patients with COVID-19 were eligible.The severity of symptoms of depression, anxiety, insomnia and distress were assessed by the Chinese versions of 9-item Patient Health Questionnaire, 7-item Generalised Anxiety Disorder, 7-item Insomnia Severity Index and 22-item Impact of Event Scale-Revised, respectively. Multivariable logistic regression and structural equation modelling was performed to identify factors associated with mental health outcomes.A total of 610 psychiatric professionals were included. 29.8% were employed in Wuhan, and 22.5% were frontline workers. A considerable proportion of participants reported symptoms of depression (461 (75.6%)), anxiety (282 (46.2%)), insomnia (336 (55.1%)) and mental stress (481 (78.9%)). Psychiatric symptoms were associated with worrying about infection  for anxiety), risks of exposure to COVID-19  for depression) and self-perceived physical health  for mental stress). Information sources of COVID-19 were also found to be both positively  for mental stress) and negatively  for mental stress) associated with mental stress. There is preliminary evidence that mental health might benefit from greater availability of mental healthcare services. The structural equation model analysis indicated that worrying about infection may be the primary mediator via which risk of exposure to COVID-19 pandemic affects the mental health of psychiatric professionals.The current findings demonstrate several pathways via which the COVID-19 pandemic may have negatively affected the mental health of psychiatric professionals in China. Provides a timely evaluation of the acute psychological impact of the COVID-19 pandemic on the mental health of psychiatric professionals in China.The large scale nature of the study means it is well powered to detect meaningful effects and allow for the control of potentially confounding variables.A sampling bias exists because of the voluntary response sampling method.The cross-sectional, observational nature of the study means it is not possible to conclusively determine whether observed associations are causal in nature.The 2019 epidemic of COVID-19 that initiated in Wuhan ,The mental health of healthcare workers in general has been affected during the immediate wake of the COVID-19 epidemic.7The specific impact of the pandemic on the mental health of psychiatric professionals is less well characterised. In the current study, a multicentre survey was performed to assess psychological distress in psychiatric professionals in China 1 week after Wuhan city entered lockdown. A brief questionnaire was designed and distributed to psychiatric professionals of several hospitals through the ‘WeChat’ group chat application, including staff of both psychiatric hospitals and psychiatric staff working in general hospitals and fever clinics. We used the responses from this questionnaire to investigate which factors were associated with an increased risk of mental health symptoms among psychiatric professionals, and whether there was any evidence of potentially protective factors.A WeChat-based online survey was completed by psychiatric professionals between 29 January and 7 February 2020, the second week after Wuhan city locked down. During the survey period, the cumulative number of confirmed and suspected COVID-19 cases was climbing exponentially .The online survey was conducted with the WeChat-based survey programme ‘Questionnaire Star’ based on a voluntary response sampling method. The target population was psychiatric professionals working in hospitals that established fever clinics or wards for patients with COVID-19. Each WeChat account of a participant was authenticated by their ID card in China. An online advert with a Quick Response code directing to the online survey was distributed in psychiatric professionals’ WeChat working groups of several provinces. Completing the questionnaire outside of working hours was advised. Prior to providing informed consent, potential participants were provided with information regarding the research project including its primary goals. After reading this information, potential participants were provided with the option to either decline or consent to take part in the study. Only those who consented were taken to the questionnaire page. Respondents could terminate the survey at any time or during any question if they wished to.No patients were involved in this study.The questionnaire consists of seven sections: basic demographic data, mental health assessment, risks of exposure to COVID-19, source of information about COVID-19, mental healthcare services (MHS) accessed, worry about infection and self-perceived physical health before the COVID-19 outbreak. The questionnaire required 15 min to complete.Basic demographic data include gender, age, marital status , educational level , location, job type (doctor or nurse), job title  and hospital type .We used four well-validated scales to assess the mental health status of psychiatric professionals. The 9-item Patient Health Questionnaire (PHQ-9), the 7-item Generalised Anxiety Disorder (GAD-7), the 7-item Insomnia Severity Index (ISI) and the 22-item Impact of Event Scale-Revised (IES-R) were used to evaluate depression, anxiety, insomnia and stress, respectively. The PHQ-9 is a self-report measure used to assess the severity of depression and has good reliability and validity in Chinese populations (Cronbach’s α=0.89).14Exposure to COVID-19 was determined by the following questions asked to psychiatric professionals:Have you been diagnosed with COVID-19?Do you manage patients diagnosed with COVID-19?Has your family been diagnosed with COVID-19?Have your friends been diagnosed?Have your neighbours (people living in the same community who may or may not know each other) been diagnosed?Does anyone living with you have suspected symptoms?In terms of personal protection, participants were asked whether they had enough personal protection equipment (PPE) and enough training for personal protection. The possible responses to each question were yes or no.The following question was used to determine which psychological services the subject had accessed: “Have you ever received the following services: psychological support materials , psychological resources available through media  or online counselling or psychotherapy ?”The following question was used to determine from which source subjects had accessed information regarding COVID-19: “Which way do you used to get information about COVID-19: relatives , social media , TV  and other (other information sources of COVID-19) and daily time (hours) spending on information of COVID-19”. Then, participants were asked how helpful the information they received were. Answer options included considerably helpful, medium helpful, slightly helpful or not helpful at all.Physical health status was determined by asking participants to compare their health status to normal people before the outbreak of COVID-19: “How do you perceive your health status compared with normal people before the outbreak?” Answer options included strong, normal or weak.Worry about infection was determined by asking participants if they worry about their vulnerability to infection of COVID-19 in workplace or at home. Possible responses were yes or no.All statistical analyses were carried out in the statistical programming language R (V.3.6.0).152 test to determine the effect of six components  on prevalence of four mental health symptoms  among psychiatric professionals.A bivariate analysis was performed first by using a χStepwise logistic regression analysis according to Akaike information criterion was then performed to examine the effects of the six components on the four mental health assessment  separately. The significance of association between the potential risk factors and outcomes were checked by analysis of variance (ANOVA) and prediction accuracy of models were counted by area under the receiver operating characteristic curve.2 test of model fit and df <3, root mean square error of approximation (RMSEA) values <0.08 and goodness-to-fit index (GFI) values >0.90, indicate acceptable models.19Finally, a structural equation model (SEM) was constructed via R package lavaan V.0.6–7P values <0.05 indicated that a difference was statistically significant.Initially, 834 completed questionnaires were received, with a response rate of 78.5%. The duration (seconds) to complete the questionnaire was recorded by Questionnaire star in WeChat. We excluded 119 questionnaires with a complete duration of <5 min (300 s) or >20 min (1200 s), to ensure that all questions had been well understood and completed consecutively by respondents. We further excluded 105 questionnaires from provinces that had recruited fewer than 20 participants. In total, 224 questionnaires were excluded, leaving 610 questionnaires for analysis. Respondents completing the included questionnaires and excluded questionnaires were comparable in age and sex.In total, 610 psychiatric professionals, including 164 (26.9%) doctors and 446 (73.1%) nurses were included in the analysis. It was found that 29.8% of these participants were employed in Wuhan and 53.3% were employed in Hubei provinces other than Wuhan; 22.5% were frontline mental health staff and 53.3% of participants were working in a tertiary hospital. The participants tended to be female (76.1%), aged 26–40 years (63.1%), married (68.2%), with an educational level of undergraduate (91.3%) and have a junior job title (62.1%), as shown in According to standard questionnaire cut-offs of the PHQ-9, GAD-7, ISI and IES-R scores, 461 (75.6%) of individuals met criteria for depression, 282 (46.2%) for anxiety, 336 (55.1%) for insomnia and 481 (78.9%) for high levels of mental stress.As shown in We found that psychiatric professionals who took part in frontline work possessed higher prevalence of all four mental health symptoms  compared with those who worked in second-line services. Treating and diagnosing infected patient , working with infected colleagues , employed in Wuhan , worse self-perceived physical health , worrying about infection  and obtaining information about COVID-19 from relatives  were also significantly associated with higher prevalence of all four mental health symptoms. Self-infection  and living with infected neighbour  were significantly associated with higher prevalence of anxiety.Access to mental health services was associated with a lower prevalence of mental health symptoms, both access to psychological support materials  and mental health services accessed through media . Obtaining information about COVID-19 from TV  was also significantly associated with lower prevalence of mental health symptoms, as shown in To explore potential risk and protective factors, stepwise logistic regression analyses on PHQ-9, GAD-7, ISI and IES-R scores separately was performed. After controlling for potential confounding variables, checking the significance of effect of each variable using ANOVA, we identified risk and protective factors as follows .Treating and diagnosing infected patient , worrying about infection , having inadequate PPE  and worse self-perceived physical health  were significantly associated with higher PHQ-9 score among psychiatric professionals. Obtaining information about COVID-19 from relatives  was also significantly associated with increased PHQ-9 score, while obtaining information from TV  was significantly associated with lower PHQ-9 score.Doctors were found to have higher GAD-7 scores  compared with nurses. Self-infection seems a primary risk factor to anxiety , and all self-infection psychiatric professionals met criteria of severe anxiety. Treating and diagnosing infected patient , working with infected colleague , living with infected neighbour , having inadequate PPE , worrying about infection  and obtaining information from other methods  were associated with increased GAD-7 score. Mental health services accessed through psychological support materials  and those who thought information about COVID-19 was helpful  showed lower GAD-7 score.Treating and diagnosing infected patients , worse physical health status  and those worrying about infection  were significantly associated with higher ISI score.Treating and diagnosing infected patient , worse self-perceived physical health  and worrying about infection  were significantly associated with higher IES-R score among psychiatric professionals. Psychiatric professionals obtaining information from relatives showed significantly higher IES-R score , while those who obtained information from TV , and those who thought information about COVID-19 was helpful  showed lower IES-R score.2 test of model fit yielded a value of 729.6, with df=253, p=0.000, χ2/df=2.88, RMSEA=0.056, GFI=0.909 and Tucker-Lewis index (TLI)=0.973, indicating a good fit. The results showed that gender, the risk factors of exposure, source of information about COVID-19 and self-perceived physical health status affected mental health through worry about infection, indicated that worrying about infection could be the primary mediator that affects the mental health of psychiatric professionals during the COVID-19 outbreak. Mental health services alleviated mental health symptoms through decreasing the worry about infection. The results are shown in Finally, we established an SEM of the association between the seven areas described in methods. The χThe current study investigated the psychological impact of COVID-19 among psychiatric professionals in China during the first months of the pandemic. The overall prevalence of depression, anxiety, insomnia and stress in psychiatric in the second week after Wuhan city locked down were 75.6%, 46.2%, 55.1% and 78.9%, respectively.In comparison with recent studies of general healthcare workers,20We identified several factors that were associated with higher psychiatric symptom burden. An increased risk of exposure to COVID-19, including treating and diagnosing infected patients was significantly associated with higher risk of mental health symptoms among psychiatric professionals. We also found that female healthcare workers had a higher risk of developing depression symptoms but not anxiety, insomnia or mental stress symptoms during the COVID-19 pandemic among psychiatric professionals. A recent meta-analysis study showed that females had a higher risk of developing psychiatric symptoms and reported lower psychological well-being during the COVID-19 pandemic, but the findings of the studies included in the published meta-analysis were not consistent.This is the first study to explore the psychological effect of different sources of information about COVID-19 on mental health among psychiatric professionals. At the early stage of the outbreak, the unpredictable nature of the pandemic was accompanied by misinformation, often driven by erroneous news reports from unofficial information sources and the public’s misunderstanding of health messages, thus causing worry and increasing the risk of mental health problems in population.To efficiently cope with psychological impact of the COVID-19 outbreak, the Chinese Government has implemented rapid and comprehensive psychological crisis interventions, including publishing psychological support materials, such as leaflets and books, establishing psychological intervention teams on site,Our study also has some limitations. First, the study is cross-sectional and does not record the mental health status before the outbreak, and cannot establish causal associations. There is a potential for a response bias given the voluntary nature of the survey. However, at least as regards occupation and gender, our sample is not substantially different from the overall workforce. Certain factors may limit the generalisability of our findings. Our study was performed in the early days of the outbreak and was concluded by the end of the second week after Wuhan city locked down. During this period, the rapid rise in number of identified and suspected cases and unprecedented scale of the lock down caused public panic and psychological stress, which may have diminished over time.3In summary, the results demonstrate that a strikingly large portion of psychiatric professionals in China suffered from mental health disturbances during the early outbreak of COVID-19. Their mental health was primarily affected by worry about being infected, risks of exposure to COVID-19 and self-perceived physical health. Unreliable information sources of COVID-19 may exacerbate mental health symptoms, and healthcare worker mental health may benefit from greater availability of mental healthcare from public and personalised mental health services.