N = 38); face-to-face and blended [FTF/blended] (N = 35)] on the reduction of maladaptive personality traits as well as the interaction between maladaptive personality patterns and the response on primary endpoints . Results indicate that both treatment settings have comparable within-group effects on the reduction of distress symptoms, while the treatment in the FTF/blended setting seems to have a stronger impact on the reduction of maladaptive traits. Further, reduction of maladaptive trait expressions was a reliable predictor of treatment response in the FTF/blended setting while explaining less variance in the online setting. Beyond the promising findings on the utility of maladaptive trait change as an outcome measure, we discuss possible applications as an information source for treatment decisions.While mental health treatments have proven to be effective for a range of mental health problems, there is comparably little research on its effects on personality disorders or difficulty (PD). New dimensional conceptualizations of PD such as the ICD-11 PD model enable the cost- and time-effective dimensional assessment of severity and style of PD. Furthermore, they constitute a promising tool to investigate PD, not only as a treatment endpoint but also as a predictive or influencing factor for mental health treatments. In this study, we investigated the effects in two different mental health treatment settings [online ( Negative Affectivity with core features such as emotional lability and poor emotion regulation, Detachment comprising limited emotional expression and intimacy avoidance, Disinhibition, e.g., impulsivity and irresponsibility, Dissociality centrally defined by self-centeredness and lack of empathy and Anankastia defined by perfectionism and rigidity. The ICD-11 PD model largely corresponds to the Alternative DSM-5 Model for Personality Disorders (DSM-5 AMPD) with respect to the 2-fold assessment of severity and style of PD, but somewhat differs in the definitions of maladaptive traits. While four of the five trait domains largely parallel  comprising an assessment of severity of personality dysfunction and maladaptive personality traits or patterns  quality of life over the course of 16 years . NeurotiAt the same time, personality traits seem to be amenable to change through clinical interventions. A recent meta-analysis investigated changes in personality traits across 207 clinical trials , these mAdditionally, personality traits also seem to influence the course and outcome of mental health treatments, with more maladaptive expressions having a worse prognosis. In their review across 99 studies, Bucher et al.  found peTaken together, maladaptive personality expressions seem to constitute a transdiagnostic and perpetuating factor for mental health issues, while at the same time being a predictive factor for treatment response and being amenable to change through clinical intervention.This exploratory research study investigated the mutual interference of maladaptive personality patterns with two different settings of psychological treatments (online and face-to-face setting). We aim to explore the following questions: Are maladaptive personality patterns according to DSM-5 and ICD-11 amenable in the treatment settings investigated in this study? If so, how is this change associated with symptom response to psychological treatment? Are there differences regarding effects on maladaptive personality patterns between interventions in the online and face-to-face setting? Are certain maladaptive personality patterns predictive of treatment response in a given setting?To these aims, we investigated indicators for maladaptive personality patterns according to DSM-5 and ICD-11 together with indicators for psychological distress at baseline and post-intervention measurement points in two different mental health settings.in vivo exposures). The final sample consisted of 38 participants who completed treatment and had available data at baseline and post-treatment, i.e., 10 or 14 weeks post-randomization. For the subsequent analyses, we used the post-measurement in week 14, with missing data obtained by available data from week 10. Average age was 44.6 years  with 24 (63%) participants being female.For the internet-based treatment sample, data were collected within a randomized controlled trial on the efficacy of an internet-based version of the Unified Protocol (UP), a transdiagnostic intervention for internalizing disorders focused on emotion regulation processes, for patients with primary anxiety, depressive, or somatic symptom disorders . ParticiSD = 15.5, range = 20–70), and 23 (65.7%) of the participants were female.The second sample consisted of participants of the Swiss trial of the E-Compared study  comparinIn the online setting, the PID5BF+ was assessed. The PID5BF+ is a 34-item self-report instrument based on the Personality Inventory for DSM-5 (PID-5), augmented with the ICD-11 personality trait domain Anankastia. The PID-5 is the official, 220-item self-report measure for the evaluation of maladaptive personality traits in five superordinate domains and 25 facets according to the DSM-5 AMPD , 33. TheN = 4,727).In the FTF/blended setting, the PID-5-SF was used. The PID-5-SF is an abbreviated 100-item version of the PID-5 with nearly identical psychometric properties . As abovIn the online setting, mental distress was assessed with the 18-item Brief Symptom Inventory , a valiIn the FTF/blended setting, mental distress was assessed with the Quick Inventory of Depressive Symptomatology . The QITo assure comparability of the two different measures for mental distress, we calculated average instead of sum scores as both scales have a natural zero point and comparable descriptives in the two samples [BSI mean = 1.07 (range = 0–2.5) vs. QIDS mean = 1.28 (range = 0.11–2.67)].d = 0.85 [CI = 0.31–1.38]).Notably, average scores on baseline maladaptive traits and mental distress were not significantly different between participants with and without available post-treatment data in both samples except for Disinhibition in the online sample with non-completers having higher scores  models with the baseline to post differences in 6 maladaptive traits plus PD severity and baseline mental distress score as independent variables and the post-assessment mental distress score as dependent variable using the  package . We calcRegularized or penalized regression models, such as LASSO-regression allow to account for high collinearity, i.e., non-independence of predictor variables. This seemed a suitable approach for 8 predictors of which seven are correlated maladaptive trait domains and one is the total average score of these maladaptive trait expressions. In their review including a comparison of methods to deal with collinearity, Dormann et al.  found LAIn a second step, to ensure interpretability and comparability of the regression coefficients, we calculated a multiple regression model with post-treatment mental distress as the dependent variable including only predictors that yielded regularized regression coefficients differing from 0, i.e., that were > 0.001.To evaluate whether maladaptive trait expression at baseline may be a useful information source for decisions concerning the selection of treatment modalities, we calculated multivariate LASSO-regression models with the reduction of mental distress in either of the two treatments, i.e., two standardized pre-to-post difference scores, one per treatment, as dependent variables. As above, in a second step, we calculated a multiple regression model only including predictors that survived the LASSO regression procedure.Mental distress levels were comparable both at the beginning and the end of the treatments but with differences in the assessment measures impeding the interpretation of significance tests. Both treatments had comparably strong pre-to-post effects on psychological symptomatology.In the online setting, a pre-to-post difference in maladaptive trait domain expressions was only found for Negative Affectivity. Conversely, all 6 maladaptive trait domains as well as the total average score showed significant change in the FTF/blended setting.d = 1.18 [1.05–2.43] and Detachment, d = 1.22 [0.99–2.25] in the online setting, while Antagonism, d = 0.82 [0.47–1.75], was significantly higher in the FTF/blended setting. At post-treatment, Negative Affectivity, d = 0.99 [0.74–2.07], Detachment, d = 1.51 [1.40–2.68] and Disinhibition, d = 0.68 [0.24–1.30] were still higher in the online setting. Psychoticism was moderately higher in the FTF/blended setting at baseline (d = 0.64 [0.17–1.11]) with a smaller difference at post-treatment (d = 0.49 [0.01–0.96]) but in both cases with significance not surviving Bonferroni correction.Maladaptive trait domain expressions at the beginning of the treatments were found to be significantly higher for Negative Affectivity, T-Score of 55.6. After treatment, there were moderate but not statistically significant differences in total average maladaptive trait scores between the treatment conditions with 0.92 [T = 55.6] in the online setting and 0.73 [T = 53.5] in the FTF/blended setting, corresponding to d = 0.48 [0.01–0.95].At the beginning of treatment, the personality dysfunction severity was comparable in both settings. In the online setting, the mean of 1.03 corresponds to a T-Score of 58.2 , in the For both settings, the results of the regularized LASSO-regression revealed only the pre-to-post difference in PD severity and the baseline mental distress score to account for a significant proportion of variance see . AccordiF = 19.8, p < 0.001, R2 = 0.53], with the baseline mental distress score explaining a larger proportion of the post mental distress variance (R2 = 0.42) than the PD severity difference (R2 = 0.10).The multiple linear regression model predicting post-treatment mental distress in the online setting by the pre-to-post change in PD severity and the baseline mental distress score revealed both indicators to have a significant impact on the post-treatment mental distress level . Here, the pre-to-post difference in personality dysfunction explained the larger proportion of post-treatment mental distress reduction (R2 = 0.49) in comparison to the baseline mental distress score (R2 = 0.16).Predicting the post-treatment mental distress score in the FTF/blended setting by the pre-to-post difference in PD severity and the baseline mental distress score, revealed both indicators having a strong impact on post-treatment mental distress . In the FTF/blended setting, multiple linear regression predicted a stronger reduction of post-treatment mental distress for lower Negative Affectivity and higher mental distress at baseline .The LASSO-regularized multivariate regression model predicting treatment response to one of the two treatments based on baseline maladaptive trait expressions yielded Negative Affectivity, Detachment, Antagonism and baseline mental distress levels to be differentially predictive of treatment response in the two treatment settings see . MultiplThe exploratory results of the present study showed that both treatments had comparably large within-group effects on the reduction of mental distress while differing in their effects on maladaptive personality traits. More precisely, change in maladaptive trait domains through mental health treatment seems to be possible in both settings, at least with respect to the self-reported maladaptive traits scores in the two study samples. In the online setting, only Negative Affectivity showed a significant change. This is in line with a central postulation of the used treatment rationale of the Unified Protocol which was explicitly developed to target neuroticism and has been shown to elicit changes on neuroticism . Further2) than in the online (10% ΔR2) treatment setting. Change in maladaptive trait domains seems therefore to be differentially intertwined with reduction in mental distress depending on the treatment setting. Although the results of this exploratory study must be interpreted with caution, an explanation for these treatment-bound differing impact factors and the stronger reduction of maladaptive personality patterns in the FTF/blended setting could be the inherently interpersonal nature of both traditional FTF psychotherapy and maladaptive personality patterns. Maladaptive personality traits are consistently associated with generalized interpersonal dysfunction (Secondly, most predictive for treatment response was not the change in single trait domains such as Negative Affectivity but the reduction of total PD severity. This finding is in line with previous research findings that severity of personality dysfunction seems to predict future comorbidity better than specific PD styles, i.e., maladaptive traits . Furtherfunction  and etiofunction . Traditifunction , indepenfunction . Followifunction .Thirdly, while baseline scores of Negative Affectivity were positively associated with the reduction of mental distress in the online setting, this association was negative for mental distress reduction in the FTF/blended setting. This finding may partly be explained by the specific neuroticism-addressing emotion-regulation components of the internet-based UP treatment making it more suitable for individuals with high negative affectivity. On the other hand, baseline Antagonism scores were negatively associated with mental distress reduction in the online setting and higher baseline mental distress levels were only positively associated with mental distress reduction in the FTF/blended setting. An explanation for this finding may be that personality factors associated with worse outcome such as disagreeableness  can be aThe present study has several limitations. First, our results and conclusions should be interpreted with caution due to small sample sizes. Sample sizes in both settings, as well as the combined sample, are too small for reliable inferences considering the mostly moderate effect sizes. Additionally, allocation to treatment settings was not randomized implying selection-bias concerning baseline scores. Second, both mental distress and maladaptive traits were assessed differently in the two samples leading to systematically differing variances impeding between-treatment comparisons. Variables were assessed in different ways in the two samples because they originate in larger previous studies that were planned and implemented independently. Third, we only analyzed the completer sample, implying a further selection effect, though baseline-differences between completers and non-completers were negligible. Fourth, we had no follow-up data to investigate if reduction in maladaptive personality patterns leads to a better prognosis for long-term remission. Fifth, in the FTF/blended setting, average treatment duration was 16 weeks compared to 10 weeks in the online setting. Consequently, the difference in personality pattern changes may also only be due to a longer treatment.Despite these limitations, our results preliminarily substantiate previous research identifying maladaptive personality patterns to play an important role, both as transdiagnostic factors as well as for the prognosis and indication of mental health treatments. Assessing the severity and style of personality dysfunction according to ICD-11 may therefore not only be a valid instrument for the diagnosis of PD but also an indicator of the degree and duration of process-based interactional experiences that an individual patient may need to profit in the long-term of a treatment. However, the question whether individuals with certain maladaptive traits such as Antagonism benefit more from treatments in the FTF setting than in an online setting is a question for further research. Future research also needs to address whether change in personality functioning leads to higher resilience and a reduced risk for relapse in the long-term.andre.kerber@fu-berlin.de.The data analyzed in this study is subject to the following licenses/restrictions: Data can be obtained upon reasonable request from the corresponding author. Requests to access these datasets should be directed to The studies involving human participants were reviewed and approved by Ethikkommission des Fachbereiches Erziehungswissenschaft und Psychologie, Freie Universität Berlin and Kantonale Ethikkommission Bern. The patients/participants provided their written informed consent to participate in this study.AK analyzed the data and wrote the initial draft, which was then edited and reviewed by CS, TK, AU, HR, TB, JB, and CK. TK, TB, AU, and HR were responsible for the data acquisition in Switzerland. CS, JB, CK, and AK were responsible for the data acquisition in Germany. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Bystander cardiopulmonary resuscitation (BCPR), early defibrillation and timely treatment by emergency medical services (EMS) can double the chance of survival from out-of-hospital sudden cardiac arrest (OHCA). We investigated the effect of the COVID-19 pandemic on the pre-hospital chain of survival. We searched five bibliographical databases for articles that compared prehospital OHCA care processes during and before the COVID-19 pandemic. Random effects meta-analyses were conducted, and meta-regression with mixed-effect models and subgroup analyses were conducted where appropriate. The search yielded 966 articles; 20 articles were included in our analysis. OHCA at home was more common during the pandemic . BCPR did not differ during and before the COVID-19 pandemic , although bystander defibrillation was significantly lower during the COVID-19 pandemic . EMS call-to-arrival time was significantly higher during the COVID-19 pandemic . Resuscitation duration did not differ significantly between pandemic and pre-pandemic timeframes. The COVID-19 pandemic significantly affected prehospital processes for OHCA. These findings may inform future interventions, particularly to consider interventions to increase BCPR and improve the pre-hospital chain of survival. This prehospital component of the “chain of survival” involves timely and seamless bystander cardiopulmonary resuscitation (BCPR), the use of automated external defibrillators (AED), as well as treatment by emergency medical services (EMS). However, the unprecedented coronavirus disease 2019 (COVID-19) pandemic had a poorly understood impact on EMS resources and was believed to have disrupted the prehospital “chain of survival” particularly layperson or bystander response4. There is tremendous scientific and public health interest in how community and EMS-related processes were altered since these confer larger survival impact relative to advanced hospital-based interventions, and the benefits of the latter are confined to those who had received timely prehospital interventions5. Understanding the impact of the COVID-19 pandemic on OHCA care processes is key to planning of future public health programs and policies to improve OHCA outcomes in the post-pandemic era and pandemic-preparedness.Out-of-hospital cardiac arrest (OHCA) is a time-critical medical emergency, in which clinical outcomes are thoroughly dependent on a well-organized “chain of survival”7. Marijon et al. reported a decrease in BCPR possibly because bystanders were more hesitant to perform CPR on possible COVID-19 cases8. This was particularly worrying since BCPR with early defibrillation may double a victim’s chances of survival9. This observation, however, was not found in some other studies11, prompting a review of the current literature on BCPR before and during the pandemic and on related variables such as OHCA at home, witnessed OHCA, and bystander AED use. EMS care processes in the pre-hospital “chain of survival” are also key factors contributing to improved outcomes in OHCA, including EMS resuscitation attempts and duration, EMS call to arrival times, and the use of various advanced life support measures such as endotracheal intubation, supraglottic airway devices, amiodarone, epinephrine, and mechanical CPR. These factors are critical in the pre-hospital management of OHCA patients before accessing advanced care12. Previously, Lim et al. suggested that EMS call to arrival times during the pandemic may have risen due to challenges such as increased personal protective equipment (PPE) requirements13. However, the impact of the pandemic on EMS care processes is unclear.Studies that assessed the impact of the pandemic on the prehospital “chain of survival”, particularly early bystander response, have reported inconsistent findings14. We hypothesized that OHCA increased in the home and BCPR rates decreased during the pandemic. Furthermore, we postulated that EMS call to arrival times increased during the pandemic.Therefore, this systematic review and meta-analysis aimed to investigate the effect of the COVID-19 pandemic on OHCA care processes and clarify the role of the pre-hospital “chain of survival” during the pandemic. While there exist previous reviews on similar topics, none have specifically focused and comprehensively reviewed the impact of COVID-19 on the pre-hospital “chain of survival”15. It is registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021274223)16.This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelinesThe search strategy was developed in consultation with a medical information specialist at NUS, Singapore. We utilized the Medical Subject Headings (MeSH) term “heart arrest” and the non-MeSH terms “sudden cardiac arrest, sudden cardiac death, out of hospital cardiac arrest (OOHCA), out-of-hospital cardiac arrest, cardiac arrest, OHCA, OOHCA, COVID-19, Coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)”. An exhaustive literature search was performed in five bibliographic databases from the date of the first reported COVID-19 case  to May 3rd, 2021: PubMed, EMBASE, Web of Science, Scopus and The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library. References of relevant articles were hand-searched to identify additional relevant studies. The search strategy is available in the Appendix The inclusion criteria were: (A) patients with OHCA during the COVID-19 pandemic; (B) articles that reported any of the following characteristics and outcomes: OHCA at home, unwitnessed OHCA, BCPR, AED use, EMS resuscitation attempted, resuscitation duration, EMS call to arrival time, use of endotracheal intubation, use of supraglottic airway, use of amiodarone, use of epinephrine, use of mechanical CPR; and (C) articles that compared the above mentioned outcomes during and before the pandemic. We ensured that there was no overlapping or repeated data from the included studies.The exclusion criteria were: (A) all articles not written in the English language; (B) all articles that did not utilize a historical control (comparing outcomes during and before the pandemic); (C) case reports; (D) case series with fewer than five patients; and (E) conference abstracts and posters.17. Two authors (Y.M and S.E.T) performed the literature search and evaluated the eligibility of studies independently. Disagreements were resolved after consensus with the senior author, A.F.W.H.The web-based platform Rayyan QCRI was utilized to perform article deduplication, screening and assessment for final eligibilityThree authors  independently extracted data from included studies to a spreadsheet. Any conflicts with data collection were arbitrated after consensus with a senior author, A.F.W.H. We extracted the following data—(A) study characteristics including first author details, year of publication, study origin, study design and population, time periods and sample sizes of (i) COVID-19 pandemic (ii) Pre-COVID-19 pandemic; (B) patient characteristics including age and gender; (C) community processes-related outcomes such as OHCA incidence at home, unwitnessed OHCA events, BCPR, and AED use; and (D) EMS processes-related outcomes such as EMS resuscitation attempted, resuscitation duration, EMS call to arrival time, endotracheal intubation and supraglottic airway, amiodarone and epinephrine, and use of mechanical CPR. If the data presented were missing or unclear, we contacted the corresponding author by email for clarification.The methodological quality of the included studies was assessed by two authors (Y.M and S.E.T) independently using the Newcastle–Ottawa Scale (NOS). The scale included eight items, and possible scores ranged from zero to nine. Studies with a score of seven or more were considered high quality.Meta-analyses were conducted for the community processes , as well as EMS processes of OHCA patients .meta 4.18–0 and metafor 2.4–0 packages with R 3.6.3 . Random-effects models were used in conjunction with the Sidik–Jonkman estimator and Mantel–Haenszel method to estimate the pooled effects of COVID-19, as substantial between-study heterogeneity was present. Forest plots displayed individual and pooled odds ratios (OR) and 95% confidence intervals (95% CI) for the binary outcomes: OHCA at home, unwitnessed OHCA, BCPR, AED use, EMS resuscitation attempted, endotracheal intubation and supraglottic airway, amiodarone and epinephrine, and mechanical CPR. For the continuous outcomes , forest plots displayed individual and pooled standardized mean difference (SMD) and 95% CI. Two-tailed statistical significance was set at p-value ≤ 0.05. The I2 statistic was used to quantify statistical heterogeneity18. This statistic indicates whether variation is more likely due to chance or study heterogeneity, with I2 values of 25%, 50%, and 75% indicating low, moderate, and high heterogeneity respectively. Whenever there was substantial statistical heterogeneity (I2 > 50%), we evaluated for outliers by performing a set of case deletion diagnostics to identify influential studies and subsequent leave-one-out sensitivity analyses. To account for possible moderators that might contribute to statistical heterogeneity, we performed univariate meta-regression with mixed-effects models and subgroup analyses for the outcome of BCPR. Publication bias was evaluated via visual evaluation of funnel plots and Egger’s regression.Data analyses were performed using the The database search yielded a total of 966 articles. After removal of duplicates, 546 abstracts were screened and subsequently 122 reports were sought for retrieval, of which 14 articles could not be retrieved. The resultant 108 full-texts were reviewed, and 20 were identified as meeting the selection criteria. The study selection process and reasons for exclusion were illustrated in the PRISMA-P 2020 Flow Diagram . All studies included were retrospective cross-sectional study design.There were a total of 67,815 patients with OHCA across the studies, of which 28,960 patients were evaluated during the COVID-19 pandemic and 38,855 patients were evaluated prior to the COVID-19 pandemic. Study sample sizes ranged from 101 to 19,303 patients. The study characteristics were summarized in Table All studies achieved a score from seven to nine on the Newcastle–Ottawa Scale, signifying high quality and low risk of bias for selection  in the COVID-19 pandemic, while Ortiz et al. reported the lowest percentage (60.5%) of patients with OHCA at home prior to the COVID-19 pandemic26. In contrast, Fothergill et al. reported the highest percentage of patients with OHCA at home in both periods during and before the COVID-19 pandemic 11. With the exception of four studies26, which showed a lower percentage of patients with OHCA at home during as compared to before the pandemic, a trend was observed where the percentage of patients with OHCA at home was higher during the COVID-19 pandemic as compared to Pre-COVID-19 pandemic (Table Fifteen studies accounted for the outcome of OHCA at homeI2 = 90%)  and before the pandemic (22.8%)21. Meanwhile, Paoli et al. reported the highest percentage in the COVID-19 pandemic (75%) and Lai et al. reported the highest percentage for Pre-COVID-19 pandemic (73.5%)   while Ball et al. reported the highest percentage (78.7%)  while Ball et al. reported the highest percentage (73%)30. Meta-analysis showed that there was no difference in BCPR during and before the pandemic        reported a higher percentage of supraglottic airway use in the COVID-19 pandemic as compared to Pre-COVID-19 pandemic (Table I2 = 97%)   Fig. A. Meanwh1%) Fig. B.27, while seven studies accounted for the use of epinephrine27. Apart from Lai et al.7, all other studies reported a higher percentage of amiodarone use in the COVID-19 pandemic relative to Pre-COVID-19 pandemic. The trend was not as obvious in epinephrine usage; four studies27 reported a higher percentage of epinephrine use during the pandemic as compared to before the pandemic, while three studies reported an inverse occurrence (Table I2 = 90%)   Fig. A. Simila3%) Fig. B.20. Baldi et al. reported a lower percentage of mechanical CPR use during the COVID-19 pandemic as compared to before the pandemic while Ball et al. reported the converse  , unwitnessed OHCA , BCPR , AED use , EMS resuscitation attempted , EMS call to arrival time , resuscitation duration , endotracheal intubation , supraglottic airway , amiodarone , and epinephrine  . Univariate meta-regression did not reveal any statistically significant moderators. Meta-regression analyses were only conducted for the outcome of BCPR as it had the highest number of studies. We did not conduct meta-regression for other outcomes due to the inadequate data (Supplementary Table Meta-regression with a mixed-effects model was performed for the outcome of BCPR to examine if the observed heterogeneity could be contributed by possible moderators such as sample size, mean age, proportion of males, proportion of patients with OHCA at residential location, GDP per country, GDP per state and population density of study region (kmA funnel plot was generated based on the outcome BCPR which had the highest number of studies, revealing no asymmetry, hence suggesting the absence of publication bias (Supplementary Fig. In this study, we elucidated several salient findings. First, there was a significant increase in OHCA occurring at home and a significant decrease in bystander AED use during the COVID-19 pandemic. Second, there was no difference in BCPR rates during the pandemic as compared to before. Third, the pandemic was associated with changes to EMS processes including a significant decrease in attempted EMS resuscitation, a significant increase in EMS call to arrival times, a significant decrease in endotracheal intubation, and a significant increase in supraglottic airway use.33. As more people are enforced to stay or work from home34, OHCA at home rates have consequently increased. Importantly, this finding also highlights that witness rates for OHCA incidence are similar during the pandemic as compared to before. This is necessary to consider for future prehospital interventions as subsequent measures should be targeted at the accessibility of services and devices and less at the detection of OHCA in the chain of survival35. This finding is supported by a statistically significant decrease in bystander AED use during the COVID-19 pandemic, which could be attributed to an increase of OHCA occurring at home37. The lack of AED availability in homes may principally explain this observation, along with inaccessibility of AEDs installed in public buildings due to the sudden closure of non-essential businesses and services by government policies36. Accordingly, new perspectives for current AED guidelines may be warranted as OHCA at home rates have increased during the pandemic, highlighting the shortcomings of current AED policies. More strategic placements of AEDs should be carried out to maximize access from individual homes, with particular emphasis on rural areas where AED accessibility is relatively more limited38. Given the potentially long-lasting lifestyle changes from the COVID-19 pandemic, the rising rates of OHCA at home should be urgently addressed.The increase in OHCA at home is consistent with stay-at-home and social distancing measures worldwide during the COVID-19 pandemic39. This result could be explained by an attitude-behavior gap whereby family members at home perform CPR despite such hesitancy40. Moreover, it could also be attributed to certain recommendations that CPR is not an aerosol-generating procedure43, thus, decreasing the likelihood for COVID-19 to be transmitted. A recent study with swine models validates such findings, where the authors found that chest compressions alone did not cause significant aerosol generation in the swine model44. However, our findings should be interpreted with caution as an analysis on BCPR rates for home versus non-home arrests could not be performed due to paucity of data. Furthermore, this result should be interpreted in light of significant statistical heterogeneity unexplained by the sociodemographic, economic status, and geographical location of the sample population in each study. Although no differences were found in BCPR before and after the COVID-19 pandemic, this does not mean that campaigns or interventions encouraging CPR during the pandemic should cease, which should instead be carefully tailored to each country’s unique response to the pandemic at the societal and individual levels46.Interestingly, we found no statistical difference in BCPR during the pandemic as compared to before. This is in contrast to previous literature, which suggested that observed decreases in BCPR resulted from fear of COVID-19 disease transmission from patient to bystanders or hesitancy among family members towards performing CPR for OHCA at home due to psychological and emotional reasons47. The COVID-19 pandemic directly led to a severe strain on ambulance resources, changes in EMS workflows, and sicker OHCA patients, possibly leading to fewer patients qualifying for EMS resuscitation in an attempt to redirect scarce resources and maximize lives saved when crisis standards of care are enforced48. Additionally, protocol changes could have exacerbated the decrease in EMS resuscitation attempts during the pandemic. For example, in Detroit, EMS protocols were amended to include the termination of resuscitation in suspected COVID-19 cases after ten minutes of resuscitation without return of spontaneous circulation25. The scarcity of resources is also consistent with the increase in EMS call to arrival times, which could be attributed to PPE requirements during the pandemic and increased ambulance travel distance for OHCA patients at home10. Cho et al. reported an emphasis on high-level PPE, consistent with an exaggerated increase in EMS call to arrival time and did not modify the significance of the effect size when excluded during leave-one-out analysis10. Although our study found a relatively smaller magnitude of SMD estimate for EMS call to arrival times, there remained a statistically significant increase in EMS call to arrival times during the pandemic. This has added importance in a time-critical medical emergency such as OHCA, where every second counts. Interestingly, the increase in EMS call to arrival times occurred despite reported road traffic reduction during the pandemic3. This suggests that while the lighter road traffic may partially improve EMS call to arrival times during the pandemic, it did not completely offset the delay from PPE donning and COVID-19 related strain on ambulance resources. More studies are required to report the time between EMS departure and arrival time in order to arrive at more definitive conclusions. Finally, a decrease in endotracheal intubation was accompanied by an increase in supraglottic airway use, likely reflecting the perceived risks of COVID-19 transmission in endotracheal intubation49. Certain protocol revisions could have also contributed to the increase in intubation use, as these guidelines recommended the use of supraglottic airways over endotracheal intubation24. While the overload of healthcare systems is to be expected during a pandemic, this should not come at the cost of worsening outcomes for non-COVID illnesses including OHCA. More needs to be done to find a balance in resource allocation when saving lives affected by COVID-19 or other non-COVID life-threatening diseases. Better preparation and predefined protocols are needed for emergency care systems to operate under resource-scarce crisis situations.The decrease in EMS resuscitation attempts was significant, contrary to previous studies19. Efforts to manage the effects of the pandemic, which may be the chief priority for public health institutions, should not come at the cost of worsening outcomes for non-COVID illnesses including OHCA. Future pre-hospital OHCA measures should also be targeted at the accessibility of services and devices and less at the detection of OHCA in the chain of survival. Systematic placement of AEDs should be carried out to maximize access from individual homes, with particular emphasis on rural areas where AED accessibility is relatively more limited50. Although no differences were found in BCPR before and after the COVID-19 pandemic, educational campaigns or interventions encouraging CPR during the pandemic should continue to be championed for and carefully tailored to each country. This would improve maintenance of personal safety on an individual level and increase empowerment of rescuers on a societal level38. The negative changes to EMS processes associated with the pandemic are worrying and suggest that better preparation and predefined protocols are needed for emergency care systems to operate under resource-scarce crisis situations, including the stockpiling and effective use of PPE51. A clear transition from non-crisis to crisis resource allocation coupled with clear public health messaging will likely be beneficial. Additionally, a centralized public EMS system may improve coordination between different stakeholders during the COVID-19 pandemic and reduce OHCA mortality rates53. However, more investigation is needed in this field. Further research is also needed to investigate measures for minimizing COVID-19 transmission during resuscitation, such as supraglottic airway use and mechanical CPR, as well as the barriers to implementing them during the pandemic.These findings hold implications for future pre-hospital interventions. A growing body of evidence demonstrates significant changes to OHCA characteristics during the COVID-19 pandemic which impact public health and urgently need to be addressedThe results of this study were robust to sensitivity analyses and incorporated data from several large OHCA registries from various countries. No publication bias was detected on visual inspection and statistical analysis. However, the findings of this study should be interpreted in the context of known limitations. All included studies were observational cross-sectional studies comparing the COVID-19 period to a historical control. Hence, results were vulnerable to confounding and should be interpreted carefully. Moderate to high statistical heterogeneity was encountered during analyses. Heterogeneity in the definition of the COVID-19 pandemic and Pre-COVID-19 pandemic may have led to varying estimates of effect size, depending on local epidemiology. Moreover, the included studies had varying time periods for the COVID-19 pandemic. Each study was unable to reflect an equal severity of the pandemic, which may have contributed to the heterogeneity encountered. Differences in study characteristics such as demographics, surveillance, and data collection processes also likely further accounted for observed heterogeneity. All included studies originated from first-world countries that comprised populations with higher income and higher socio-economic status. Hence, study results may be limited in terms of generalizability despite providing key insights into OHCA during the COVID-19 pandemic.However, this study is, to our knowledge, one of the first few systematic reviews and meta-analyses to examine the impact of the COVID-19 pandemic on community and EMS care processes. It represents a global body of literature that may inform future prehospital interventions and guide the interpretation of changes in OHCA characteristics during the COVID-19 pandemic.BCPR rates remained unchanged before and during the COVID-19 pandemic, while outcomes of OHCA in the home and bystander AED increased. Ambulance processes remained largely unchanged, although EMS resuscitation attempts decreased and call to arrival times increased slightly. These findings may inform future interventions, particularly to consider interventions to increase BCPR and improve the pre-hospital chain of survival for future implementation.Supplementary Information.


Low- and middle-income countries have a high burden of respiratory syncytial virus lower respiratory tract infections. A monoclonal antibody administered monthly is licensed to prevent these infections, but it is cost-prohibitive for most low- and middle-income countries. Long-acting monoclonal antibodies and maternal vaccines against respiratory syncytial virus are under development.We estimated the likelihood of respiratory syncytial virus preventive interventions  being cost-effective in Mali.We modeled age-specific and season-specific risks of respiratory syncytial virus lower respiratory tract infections within monthly cohorts of infants from birth to six months. We parameterized with respiratory syncytial virus data from Malian cohort studies, as well as product efficacy from clinical trials. Integrating parameter uncertainty, we simulated health and economic outcomes for status quo without prevention, intra-seasonal monthly administration of licensed monoclonal antibody, pre-seasonal birth dose administration of a long-acting monoclonal antibody, and maternal vaccination. We then calculated the incremental cost-effectiveness ratio of each intervention compared to status quo from the perspectives of the government, donor, and society.At a price of $3 per dose and from the societal perspective, current monoclonal antibody, long-acting monoclonal antibody, and maternal vaccine would have incremental cost-effectiveness ratios of $4280 , $1656 (95% CI $734 to $9091), and $8020  per disability-adjusted life-year averted, respectively.In Mali, long-acting monoclonal antibody is likely to be cost-effective from both the government and donor perspectives at $3 per dose. Maternal vaccine would need higher efficacy over that measured by a recent trial in order to be considered cost-effective. The eff2.4We derived medical and hospitalization costs from a 2013 cost-effectiveness study conducted as part of the Mali maternal influenza vaccine clinical trial  for each intervention compared to the status quo was calculated as Δc/Δe, where Δc is the difference in economic costs between intervention and status quo, and Δe is the change in health outcomes. We did not conduct a head-to-head comparison of products, as the final assortment of choices available to countries is not yet certain.We integrated parameter uncertainty into our analysis using a Monte Carlo approach with 10,000 independent trials. For each trial, one value was randomly sampled from every distribution of probabilities and costs. We then calculated the health and economic outcomes associated with status quo and each intervention, holding parameters constant across each arm. The 95% confidence intervals for any given outcome were then defined as the range encompassing 95% of the values produced across all trials. The point estimate reported for each outcome is the value produced by executing the simulation using the point estimate specified for each input parameter.For evaluating the probability that an intervention would be cost-effective across a range of values for willingness-to-pay (WTP) for DALYs, we applied a net health benefits framework 2.6We performed a series of univariate analyses to identify which parameters would have the greatest influence on the results. We varied each individual parameter between its lower and upper 95% confidence limits, with all other parameters held at their point estimate. We then recorded the incremental cost-effectiveness ratio for each product at each limit.2.7We conducted six secondary analyses to assess the sensitivity of our conclusions to changes in model structure and assumptions . For eachttps://r-project.org).All analyses were performed using R 4.0.2  DALYs, 1059 (95% CI 201 to 2354) DALYs, and 146 (95% CI 26 to 331) DALYs, respectively. The health impact of each intervention is sensitive to changes in coverage rate A. At a pFrom the societal perspective, the ICER associated with each intervention would be $4280 , $1656 (95% CI $734 to $9091), and $8020  per DALY averted, respectively B. The coWe evaluated the relationship between WTP for a DALY and intervention cost-effectiveness from the donor and government perspectives independently. At a product price of $3 per dose, long-acting mAb is preferable with greater than 50% likelihood of being cost-effective from the donor perspective at WTP above $1521 per DALY C. For shWe conducted a series of one-way sensitivity analyses to identify the parameters whose variance had the largest influence on the ICER. The most influential parameter across interventions was the inpatient case fatality rate, capable of modifying the ICER by up to 315% over the point estimate B. Parame3.11.If maternal vaccine efficacy and duration were replaced with the WHO preferred product characteristics for a maternal RSV vaccine, the vaccine health impact would increase by 102%. A maternal vaccine meeting WHO preferred efficacy and duration would have an ICER of $3901  per DALY averted.2.If maternal vaccine efficacy were replaced with overall RSV-F vaccine trial results instead of South Africa site-specific results, product efficacy would decrease and the ICER would increase to $10,946  per DALY averted.3.If long-acting mAb were also given during a scheduled routine pediatric immunization visit to older infants who would have been ineligible for the seasonal birth dose based on their birth month, more infants would be protected during the RSV season. However, RSV mortality rates are lower for these older infants, so the ICER would increase to $1783 (95% CI $852 to $9618) per DALY averted.4.If maternal vaccine were given to pregnant women during a pre-seasonal campaign instead of year-round, then the ICER would decrease to $5354  per DALY averted.5.If the model included RSV-URTI health and economic outcomes, then health impact would increase for each intervention. Short-acting mAb, long-acting mAb, and maternal vaccine would have ICERs of $3475 , $1071 (95% CI $543 to $5473), and $7127  per DALY averted, respectively.6.If all infants with RSV-LRTI were to receive appropriate medical care, then the costs associated with RSV-LRTI illness would be higher than base case estimates. Short-acting mAb, long-acting mAb, and maternal vaccine would have ICERs of $3938 , $1441 (95% CI $479 to $7067), and $7733  per DALY averted, respectively.We conducted six secondary analyses to assess changes in model structure and assumptions .1.If mat4We estimated that if short-acting mAb , long-acting mAb , or maternal vaccine (year-round) programs were implemented in Mali, the incremental cost to society would be $4280, $1656, and $8020 per DALY averted, respectively. This indicates that long-acting mAb may provide better value than either short-acting mAb or maternal vaccine in Mali and similar low-income countries. We evaluated the probability of each intervention being cost-effective across a broad range of willingness-to-pay values from government and donor perspectives. From the government perspective, implementing long-acting mAb is likely to be cost-effective at willingness-to-pay values approaching the per capita GDP of Mali. The per capita GDP has been a commonly used threshold for health intervention cost-effectiveness In addition to providing sufficient value for money, new health interventions must be affordable In our secondary analyses, we assessed multiple alternative delivery and product performance scenarios. Our base case findings were generally conservative, and the alternatives led to lower incremental cost-effectiveness ratios for all interventions. In practical terms, if one or more of these alternative scenarios were true, then the RSV preventive interventions would more likely be cost-effective. As the exception, replacing the South African site-specific vaccine efficacy results from the RSV-F vaccine trial with overall efficacy results would raise the incremental cost-effectiveness ratio. In that trial, the overall 39.4% efficacy (95% CI 5.3 to 61.2%) against the primary endpoint, medically significant RSV-LRTI up to 90 days of life, did not achieve statistical significance The greatest strength of our study is use of country-specific RSV epidemiological and cost information. We used RSV incidence estimates from household surveillance standardizing identification of community cases. Nevertheless, our RSV incidence estimates came from a single full year of surveillance in urban Bamako, which were high compared to incidence estimates elsewhere While RSV-LRTI is a high burden disease, the only licensed RSV-LRTI preventive intervention is cost-prohibitive for most LMICs. Future long-acting mAb and maternal vaccines have the potential to address this unmet global health need The authors alone are responsible for the views expressed in this publication, and they do not necessarily represent the decisions, policy, or views of their institutions.This work was financially supported by grant 1,088,264 from the Bill and Melinda Gates Foundation. The funding source had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.https://github.com/MCFitz/RSV-CEA-MaliModel code is available at The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


To guide the efficient and effective provision of mental health services to clients in Central West and Far North Queensland, we surveyed preferences for face-to-face or in-person contact.A clinician-designed survey of contact preferences was offered to 248 clients of mental health services in Far North and Central West Queensland in mid-2020. With the onset of COVID-19, the survey was modified to measure the impact of the pandemic.Just over half of the services’ clients participated in the survey (50.4%), of whom more were female (63.2%). Of the participants, 46.3% in Far North and 8.6% in Central West Queensland identified as Indigenous. Strong resistance to telehealth before the pandemic across groups (76%) was moderated during COVID-19 (42.4%), an effect that appeared likely to continue past the pandemic for Central West clients (34.5%). Far North clients indicated their telehealth reluctance would return after the pandemic (77.6%).Our results suggest that remote Australians strongly prefer in-person mental health care to telehealth. Although the COVID-19 pandemic increased acceptance of telehealth across regions while social distancing continued, there was evidence that Indigenous Australians were more likely to prefer in-person contact after the pandemic. On the emergence of COVID-19 in 2020, we modified the survey to explore whether the pandemic had influenced immediate and future contact preferences.This project was deemed a low-risk quality assurance project by the Far North Queensland Human Research Ethics Committee (review number 1499 AB).This study surveyed Queensland clients accessing remote mental health services operated by the Royal Flying Doctor Service (RFDS) in Far North and Central West Queensland (FNS/CWS). Both services comprise mental health nurses, social workers, occupational therapists and psychologists providing culturally appropriate, evidence-based, psychological therapies to individuals who present with mild to moderate mental health needs.Remote Australian communities have distinctly different service accessibility and disease outcomes. The FNS and CWS are representative of the diverse populations supported by the RFDS, including a higher proportion of Indigenous clients in FNS than CWS.All current adult clients (>17 years old) of FNS and CWS in RFDS’ electronic medical record were included in the sample.Individuals in hospitals, nursing homes, prisons, hotels and hostels at the time of the survey, and visitors usually residing outside Australia, were excluded.Three attempts were made to contact participants by phone by four FNS/CWS clinicians. Respondents were asked to complete a survey, with verbal consent obtained from each participant to record, collate, and present their answers in summary form.Consenting clients were asked questions created by consensus among senior clinicians (including JM). Answers were recorded in text and responses coded by interviewers .Between May and June 2020, attempts were made to contact 248 clients, with a final sample of 125 participants (50.4%). Of 123 non-participants, 25 had no recorded phone number, 93 did not respond after three attempts, and six declined.n = 81; 54.7%) than CWS  partly because more clients had no recorded phone number .Non-participation was higher in FNS (Continuous variables were summarised as medians and interquartile ranges (IQR). Categorical variables were summarised as counts and proportions. We used chi-square goodness of fit to compare proportions with a significance threshold of 0.05.Statistical analyses were performed using the statistical software package R version 3.5.1. .Participant characteristics are summarised in n = 95; 76.0%) with no differences (p > .05) between FNS and CWS clients. COVID-19 affected preferences, with 44 clients (35.2%) preferring telehealth to face-to-face consultations during the pandemic, and 53 (42.4%) accepting telehealth after the pandemic. CWS clients were significantly (p < .05) more likely to report greater acceptance of telehealth after the pandemic  than FNS clients   .p < .05) higher identification in the FNS . Both groups preferred face-to-face services absent a pandemic. A higher proportion (p < .05) of Indigenous clients preferred that consultations occur via telehealth only during the pandemic . A significantly (p < .05) lower proportion of Indigenous clients wanted telehealth beyond the COVID-19 pandemic  participants identified as Indigenous, and 89 (71.2%) did not, with significantly  engagement for Indigenous people.13 Most clients strongly preferred in-person contact for high-impact care such as initial assessment, particularly in crisis, or care transitions. Telehealth use during the pandemic may reduce resistance for CWS clients after the pandemic. These results highlight the importance of research suggesting that telehealth may increase equitable access to care in rural and remote Australia with sufficient attention to demographics, stage and severity of illness, social supports, perceived efficacy, and technological factors such as service reliability.13 It appears likely that greater resources will be needed the more remote the client, to overcome barriers like limited familiarity with/access to technology and less opportunity to develop trusting relationships with clinicians. Training and models of care appear vital in preparing and engaging clinical staff in effective provision of telehealth services.14Thus, both FNS and CWS clients preferred telehealth in some situations, particularly with elevated in-person risks; other research has found greater tolerance for routine appointments where telehealth avoids significant travel.10 our results and previous research suggest specific groups may continue to face barriers to access.15 Pending evidence that telehealth alone or in combination is as effective as in-person care, we recommend that reliance on telehealth be treated as a key indicator of overall gaps in care for remote populations.Finally, we recommend that close monitoring of the uptake of telehealth in rural and remote Australia be used to strategically address gaps in service provision. While COVID-19 may have reduced telehealth resistance for some clients,The main limitations associated with this study included a non-validated survey created for service development; service providers collecting responses; and a high non-participation rate with non-responders likely to differ from responders, potentially leading to bias.Provision of mental health services in remote Australia differs dramatically to services delivered in major city areas, demanding tailored and culturally appropriate services. Recognising the need to balance efficiency and effectiveness for our diverse client populations, we sought to determine whether face-to-face or telehealth provision was preferred by our clients in remote Queensland. Our results suggest that Indigenous Australians were more motivated to maintain social distancing through telehealth during the pandemic, but also more likely to resist telehealth after its resolution. This pattern indicates that there may be an opportunity to use telehealth to improve access to mental health care in rural and remote Australian regions, but realising these benefits will require a systematic approach involving engagement, training, and close monitoring.


Robust assay development for SARS-CoV-2 serological testing requires assessment of asymptomatic and non-hospitalised individuals to determine if assays are sensitive to mild antibody responses. Our study evaluated the performance characteristics of two high-throughput SARS-CoV-2 IgG nucleocapsid assays (Abbott Architect and Roche) and The Binding Site (TBS) Anti-Spike IgG/A/M ELISA kit in samples from healthcare workers (HCWs). The 252 samples were collected from multi-site NHS trusts and analysed for SARS-CoV-2 serology. Assay performance was evaluated between these three platforms and ROC curves were used to redefine the Abbott threshold. Concordance between Abbott and TBS was 66%. Any discrepant results were analysed using Roche, which showed 100% concordance with TBS. Analysis conducted in HCWs within 58 days post-PCR result demonstrated 100% sensitivity for both Abbott and Roche. Longitudinal analysis for >100 days post-PCR led to sensitivity of 77.2% and 100% for Abbott and Roche, respectively. A redefined Abbott threshold (0.64) increased sensitivity to 90%, producing results comparable to TBS and Roche. The manufacturer’s threshold set by Abbott contributes to lower sensitivity and elevated false-negative occurrences. Abbott performance improved upon re-optimisation of the cut-off threshold. Our findings provided evidence that TBS can be used as bespoke alternative for SARS-CoV-2 serology analysis where high-throughput platforms are not feasible on site. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has led to a global pandemic with more than 183 million confirmed infections and 3.9 million fatalities . In the UK, these were rolled out as generic assays, as part of a wider national screening programme to determine seroprevalence in healthcare workers and to determine prior SARS-CoV-2 exposure in clinical settings. The mandatory and fast-tracked deployment of such assays meant that health institutions and requestors did not have access to extensive assay performance characteristics to make informed choices. The urgent need to better understand SARS-CoV-2 seroprevalence during the first wave of the pandemic led to regulatory bodies, such as the Food and Drug Administration (FDA) and the Medicines and Healthcare products Regulatory agency (MHRA), to approve the Abbott Architect nucleocapsid (NC) IgG assay (hereon referred to as Abbott)  and ElecsysThis study was conducted at a time when no licensed SARS-CoV-2 vaccines were available; therefore, positive antibody responses correlated with natural infection. It is well known that following SARS-CoV-2 infection, humoral responses elicit an early response against both the NC and spike proteins . Such a A comparative evaluation of the above immunoassays was conducted at two different sites: Queen Alexandra Hospital, Portsmouth Hospitals University NHS Trust (PHU), and the Dudley Group of Hospitals NHS Foundation Trust (DGH). At PHU, this study was approved by Portsmouth Hospital NHS Trust Research Ethics Committee. Serum samples (n = 188) were collected that had been provided as part of the SIREN research study . Healthcare workers aged 18 years or older provided fortnightly blood samples for SARS-CoV-2 serology surveillance. Only five participants had a positive SARS-CoV-2 RT-PCR prior to SIREN enrolment. At DGH, serum from healthcare workers (n = 64), aged 18 years or older, was collected; 39 samples were confirmed RT-PCR-positive for SARS-CoV-2 and 9 were RT-PCR-negative and symptom-negative for SARS-CoV-2 . ® Anti-SARS-CoV-2 IgG nucleocapsid immunoassay  at Poole NHS Trust. Samples from DGH were analysed using the Abbott nucleocapsid IgG assay  and further evaluated using the Elecsys Anti-SARS-CoV-2 IgG nucleocapsid immunoassay . Assays were conducted in accordance with the manufacturers’ standard operating procedures by HCPC-registered laboratory staff in laboratories that held United Kingdom Accreditation Service accreditation. All assays were conducted with specified controls and calibrants using clinical cut-off thresholds for negative and positive as determined by the manufacturers. Samples from PHU were initially analysed for SARS-CoV-2 antibodies at the Department of Medical Microbiology, PHU, using the Abbott nucleocapsid IgG assay  as part of the SIREN study. Samples were identified as positive or negative based on the manufacturer’s cut-off . Samplesg. Supernatant (0.5–1 mL) was derived and made up into sample aliquots, which were stored at −20 °C until they were processed by the respective immunoassay. Samples were limited to fewer than three freeze-thaw cycles. Primary serum separator tubes were stored at 2–8 °C for up to seven days after venepuncture. Selected samples for each run were derived within this seven day period and primary samples were centrifuged for 10 min at 3500× t-test was employed to determine the significance of result outcomes produced by each immunoassay. Sensitivity and specificity with exact binomial 95% CI for assays was carried out by Fisher’s exact test. Assessment of agreement between immunoassays was conducted by concordance (percentage) and by ƙ-Cohen. Receiver operator characteristic (ROC) curves defined trade-offs in assay sensitivity and specificity for Abbott immunoassay. Analyses were performed using Graphpad Prism v9.0.1  and SPSS v27.0 . Fisher’s exact test was used to evaluate categorical data between immunoassays, whereas Chi-squared analysis was used to evaluate categorical data as a three-way comparison method. One-sample This study was conducted based on service evaluation, which did not require ethical approval. Samples were derived from altruistic healthcare volunteers and were designed for assay verification. All samples were derived after informed consent was gained from volunteers.p < 0.0001). Of the samples reported as negative using the Abbott assay (n = 131), 59 were reported as positive using the TBS assay  found concordant results in 125 samples 66.4%, A, demonsp < 0.0001, Of these 59 discordant samples between Abbott and TBS analysis, 48 samples were sent to Poole NHS Trust for analysis using the Roche Elecsys Anti-SARS-CoV-2 IgG nucleocapsid assay. Only one sample result (1/48) was in concordance between Roche and Abbott, demonstrating poor agreement . whereas all 48 samples analysed using Roche produced outcomes that were 100% in agreement with results generated from TBS. Comparative analysis of 48 samples across the three immunoassays demonstrated that Abbott reported negative outcomes in 45 samples, whereas negative outcomes were only observed in 4 samples from TBS and Roche. Overall, a significant difference in outcomes was generated by Abbott in comparison to Roche and TBS immunoassays  within 58 days of registering a RT-PCR result or the onset of COVID-19 symptoms . Further, 16 samples were collected from HCWs where RT-PCR analysis was not performed and showed no signs and symptoms of COVID-19 infection; these were classified as presumed COVID-19 negatives. Amongst these samples, 28 were followed for >100 days post-PCR result or symptom onset . In samples analysed within ≥19–≤58 days, the Abbott and Roche assays showed 100% concordance and perfect agreement (ƙ-Cohen: 1.000). All assay characteristics for both the Roche and Abbott assays were identical ; both asSamples analysed after >100 days showed a concordance of 79% (22/28) with a moderate agreement . Of the six discordant samples, which were reported as negative using the Abbott assay, was shown to be positive using the Roche assay. Of these, 5/6 were PCR-positive at initial testing, and the sample that was PCR-negative tested positive in both assays at the earlier timepoint. p < 0.0001) in comparison to the Roche assay. To further interrogate the assay performance, the samples for which low positive results were recorded  using the Roche assay were compared to the result generated using the Abbott assay . ConcordThe above analyses allowed us to define the optimal threshold enabling concordance and agreement between the three assays . Based op = 0.0621, Implementation of this redefined threshold to data obtained at PHU (n = 188 samples) gave a concordance of 82% (155/188) between the Abbott and TBS assays, where outcomes between assays were not significantly different  at two different sites and evaluated the performance, with a focus on assay sensitivities, conferred by the different SARS-CoV-2 antibody assays: TBS, Abbott and Roche. Samples from HCWs were stratified according to the data available at each site. At Portsmouth University Hospital (PHU), samples were stratified into positive and negative as reported by the Abbott assay, and were later evaluated using the TBS assay. As samples from HCWs were collected during the first wave, mass RT-PCR testing was not underway; thus, RT-PCR data were not available for most of these participants. Samples collected at DGH were stratified into COVID-19-positive and -negative samples according to RT-PCR. At both sites, concordance and agreement of SARS-CoV-2 serology were compared between the different immunoassays. Significant discrepancies were identified between the Abbott and TBS assays, with only 66% concordance found. Analysis of discrepant samples using the Roche assay showed perfect agreement with the TBS assay, whilst only one result was concordant between the Roche and Abbott assays. This highlighted the potential for the significant underestimation of seroprevalence using the Abbott assay. Of note, the sensitivity and specificity  of the Abbott and Roche assays were identical in samples tested at ≤58 days post-PCR or symptom onset, but differed significantly in samples tested at >100 days post-PCR or symptom onset (77.3% by Abbot compared to 100% by Roche). As SARS-CoV-2 antibody levels naturally wane over time , this woWe hypothesised that the reasoning behind the lower sensitivity seen in Abbott was primarily influenced by the high cut-off threshold set by the manufacturer. Such speculation was supported by our findings, as using ROC analysis we defined a cut-off of 0.64, which gave a sensitivity of 90.0% and showed good agreement with the Roche and TBS assay. Whilst it does not meet the MHRA assay stipulation of 98% sensitivity and specificity , the optOur findings are supported by a recent study that used anosmia and ageusia reported by HCWs as a high pre-test probability of mild and asymptomatic COVID-19 infections . CorrelaFurthermore, the low sensitivity of the Abbott assay was also demonstrated in results from the Spanish national serologic survey , which tAnother explanation for the seroprevalence underestimation observed in this Spanish population could be due to the sampling time used in the study (14 days post-symptom onset). Given the dynamics of humoral responses, 14 days post-viral challenge may not be sufficient time to prompt an effective adaptive response. Thus, we recommend that any future sero-epidemiological studies choose a sampling point post-symptom or PCR result that enables apt time for the development of detectable antibodies. Whilst sensitivity and specificity are crucial parameters for any serological assay, estimating the PPV and NPV is useful when determining clinical and sero-epidemiological utility. Our data demonstrate that Abbott’s low NPV (0.5) is not sufficient to rule out an individual’s recent exposure to SARS-CoV-2, which calls into question the utility of the assay when determining seroprevalence. As this study demonstrated, the TBS assay demonstrated enhanced sensitivity, as it was able to detect low-level antibody responses. This was supported by a recent study demonstrating that the TBS assay was able to detect antibody responses in non-hospitalised asymptomatic COVID-19 patients and patients with mild disease [The current licenced COVID-19 vaccines target the Spike protein of SARS-CoV-2, consequently eliciting humoral responses against the Spike protein. However, Roche and Abbott assays both measure antibodies against the SARS-CoV-2 nucleocapsid protein; thus, they may not be of use in determining vaccination responses. Uniquely, the TBS assay detects SARS-CoV-2 antibodies against the trimeric spike protein, which is the predominant immune response produced in response to SARS-CoV-2 vaccination. It is our belief that the longitudinal measurement of antibody responses following vaccination should be conducted using multiple assays that measure antibodies against the spike protein, and that this should be done alongside frequent RT-PCR testing. Such experimental design may allow the determination of protective antibody levels, as well as cross-comparative evaluation of the performance of several anti-spike serological assays. We envisage this as a multi-national study, analogous to the current SIREN study. Such studies are urgently required. Nevertheless, we believe nucleocapsid assays still have a role in sero-epidemiological surveillance. We envisage dual serological testing from use of nucleocapsid and spike assays. This will enable the identification of new seroconverts from natural infections and the monitoring of vaccination responses in niche clinical scenarios, such as in poor vaccine responders or the immunocompromised. It is paramount that proficient clinical interpretation is available in sites utilising such diagnostic strategies. Moreover, we have provided evidence here of the enhanced sensitivity of the TBS assay, which can be utilized as a viable alternative that meets bespoke clinical and possible geographical needs where high-throughput assays are unavailable on site.The present study has some limitations. Firstly, our sample sets may under-represent ethnic groups, did not comprise children, and did not capture sufficient clinical metadata required for full clinical and analytical result interpretation. We propose a further study to be conducted, where, along with the participant’s PCR status and clinical symptoms, the investigation of these immunoassays to detect responses in asymptomatic and mild cases should be evaluated to deduce the clinical sensitivity of different immunoassays. Whilst limited, the study highlights that the TBS assay showed enhanced sensitivity in detecting mild and asymptomatic antibody responses . We demonstrate here that the Abbott manufacturer’s cut-off threshold leads to a significant increase in false-negative outcomes, which contributes to the underestimation of seroprevalence. The manufacturer’s cut-off at 1.4 overexaggerates the dynamics of antibody waning, as seropositivity transitions into seronegative results much more quickly in participants analysed by Abbott in comparison to Roche and TBS. Our findings provide evidence that the Abbott manufacturer’s threshold should be redefined , which increases sensitivity (90%) and reduces the incidence of false negatives.


Selection of proper antibiotics for blood culture-negative infective endocarditis (BCNIE) is difficult due to limited data on antibiotic regimens for BCNIE in existing literature. The aim of this study was to compare ampicillin-sulbactam, other β-lactams antibiotics, and vancomycin among patients with BCNIE to determine the proper antibiotic regimens. This retrospective study included adult patients with BCNIE admitted to Severance Hospital from November 2005 to August 2017. Patients were classified into three groups as, treated with ampicillin-sulbactam, other β-lactams, and vancomycin. The primary outcome was 1-year all-cause mortality. A total of 74 cases with BCNIE were enrolled in this study. There were no statistically significant differences in clinical characteristics between the three groups. One-year mortality did not significantly differ between the study groups either. Further, in-hospital mortality, 28-day mortality and overall mortality showed no difference. However, Cox-regression analysis showed nosocomial infective endocarditis as an independent risk factor and a protective effect of surgery on 1-year mortality. This study showed no clear difference in the outcomes of BCNIE as per the antibiotic therapy but suggested the beneficial effect of surgical treatment. With increasing global concern of antimicrobial resistance, it might be reasonable to select ampicillin-sulbactam-based antibiotic therapy while actively considering surgical treatment in BCNIE. Despite significant improvements in the management of infective endocarditis (IE), it is still associated with a high mortality rate . For sucHowever, as per a previous study, blood culture-negative infective endocarditis (BCNIE) accounts for 31% of all cases of IE . A negatIn the case of BCNIE, clinicians take into consideration all the likely pathogens based on the patient’s status and local epidemiologic data. Two major guidelines on the management of IE have described several considerations for the choice of empirical antibiotic therapy in IE ,3. The KAccordingly, the choice of antibiotics for management of BCNIE is varied among physicians. The objective of this study was to compare treatment outcomes of ampicillin-sulbactam, other β-lactam antibiotics, and vancomycin among patients with BCNIE in a tertiary care hospital in South Korea to determine the proper antibiotic treatment of BCNIE. We also sought to identify other factors associated with treatment outcomes of BCNIE.A total of 419 patients with IE were identified during the study period. Of these patients, 345 patients were excluded for the following reasons: 318 patients were excluded due to identification of the causative pathogen on blood cultures, 26 patients were excluded as they received combination antibiotic therapy and 1 patient diagnosed with nonbacterial thrombotic endocarditis during follow-up was also excluded from the analysis . FinallySeventy-four cases were finally selected with median age of 54.5 years. Of these 55.4% were male, 77.0% cases were of community-acquired IE and 87.7% were native valve endocarditis (NVE). Two patients with prosthetic valve endocarditis (PVE) had received valve replacement within 1 year of diagnosis. There was no statistically significant difference in clinical characteristics including valve status and Charlson Comorbidity Index between the three groups . The nosClinical outcomes of the three groups are summarized in p = 0.58, log-rank). As secondary outcomes, in-hospital mortality and 28-day mortality also showed insignificant differences   . There wog-rank) .Multivariate cox analysis with backward elimination showed a higher risk of 1-year mortality among BCNIE patients in nosocomial infection cases (adjusted hazard ratio (HR) 6.14, CI 95% 1.41–26.69) and protective effect of surgical intervention  . VariablWe compared clinical outcomes among patients with BCNIE treated with ampicillin-sulbactam, other β-lactam antibiotics, and vancomycin. In our study, clinical characteristics between the three groups were found to be comparable and the clinical outcomes in the three treatment groups did not show significant differences either. However, results of the Cox regression analyses revealed the beneficial effect of surgery on 1-year mortality.Although scarce, there are a few studies in the existing literature on antibiotic selection in BCNIE. Werner et al. in their research, observed survival benefit with aminoglycoside therapy . This stRecent decades have seen the rise in antimicrobial resistance become a global threat . AntimicStaphylococcus aureus remains the dominant pathogen in the epidemiology of IE and methicillin-resistant Staphylococcus aureus (MRSA) accounts for a sizeable portion of S. aureus worldwide. Consequently, clinicians treating patients with BCNIE frequently consider the possibility of MRSA being the causative pathogen out of caution and consider it apt to administer vancomycin during treatment. However, several studies have shown that the proportion of S. aureus in BCNIE is quite less (2–5%) and below the level for concern [S. aureus, the proportion of MRSA in BCNIE might be reduced further.e less 2–% and bel concern . ConsideEnterococcus is also a dominant pathogen in the epidemiology of IE. As a vancomycin-based regimen is recommended for treating ampicillin-resistant enterococcal infective endocarditis, concern regarding ampicillin-resistant Enterococcus might prevent clinicians from selecting an ampicillin-sulbactam-based regimen. If regional epidemiological data indicate a high rate of ampicillin resistance in Enterococcus, using molecular methods such as Western immunoblotting might aid pathogen identification, and a vancomycin-based regimen would be a reasonable initial choice [Enterococcus faecalis and 7 of Enterococcus faecium) were confirmed in our institute during the study period, ampicillin resistance was confirmed in only one patient with E. faecium infective endocarditis. Additionally, in E. faecalis, which accounts for most enterococcal IE cases, the ampicillin resistance rate is low in South Korea [l choice . In thisl choice . Howeverth Korea ,20. ThesAcinetobacter baumannii and Pseudomonas aeruginosa, which are another set of problematic hospital acquired pathogens [In addition, reducing unnecessary use of the other broad-spectrum β-lactam antibiotics is important keeping in mind the rise in antimicrobial resistance worldwide. Global dissemination of carbapenem-resistant Enterobacteriaceae (CRE) has been observed and exposure to carbapenem and cephalosporin were the most frequently mentioned risk factors associated with CRE acquisition . Severalathogens . In thisp-value 0.023) and thus, it can be stated that surgical treatment in BCNIE might be considered in the same manner as in IE.The protective effect of surgery for survival in patients with IE has been widely accepted by several authors ,24,25. Lp-value 0.015).Several studies reported poor outcome of nosocomial IE with reported mortality of 27–82% ,29. In oCoxiella burnetii and Bartonella species [C. burnetii and Bartonella species have been rarely reported in South Korea [It is obvious, in case of BCNIE for clinicians to consider fastidious or intracellular pathogens as possible aetiologies. Several studies on BCNIE have shown a considerable proportion of these pathogens like  species ,26,30. Hth Korea ,32. In ath Korea ,33. TherC. burnetii and Bartonella species was rarely performed in our study. Another limitation of our study is the relatively small sample size due to the inclusion of patients from a single-institution only. Thus, further studies with more patients are needed to clarify the choice of first line antibiotic therapy in BCNIE. However, given the low prevalence rates of MRSA and ampicillin-resistant enterococci, a similar conclusion would likely be reached with a larger study population. As mentioned above, MRSA is not common; Enterococcus faecalis accounts for more than 90% of cases of enterococcal infective endocarditis and its resistance rate to ampicillin is low, even in nosocomial infection [This study has a few limitations. First, the majority of BCNIE cases in our study were that of NVE. Among the 9 PVE patients, 2 received valve replacement within 1 year. Therefore, the conclusion of our study might not be applicable to PVE patients. Second, as the epidemiology of IE may vary regionally, our conclusion based on single-institutional data may not be generally applicable. Still, we maintain our conclusion is sustainable regarding the main causative pathogens of IE are similar globally ,34.Thirdnfection ,35. LastThis retrospective study enrolled adult patients diagnosed with IE admitted to Severance Hospital, a large tertiary-care teaching hospital in South Korea, from November 2005 to August 2017. Patients were included if they met the following criteria: (1) Patients above 17 years; (2) diagnosed with IE and admitted to Severance Hospital; and (3) No isolated pathogen from either blood culture or valve tissue culture obtained from patients who underwent surgery. Patients were excluded if they met the following criteria: (1) Patients who received combination antibiotics therapy and (2) diagnosed with non-bacterial thrombotic endocarditis.IE was defined as definite or possible according to the modified Duke criteria . The insPatients were classified into three groups, based on the treatment received on the index date as: (a) treated with ampicillin-sulbactam, (b) treated with other β-lactams  and (c) treated with vancomycin. The index date was defined as the date when the first blood culture revealed no microbial growth. Ampicillin-sulbactam and vancomycin groups were assigned since they were recommended in the treatment guidelines. As there were many cases of administration of antibiotic therapy outside the guidelines, we defined a group as treated with other β-lactams, although this is the not recommended antibiotic therapy for BCNIE as per the guidelines but is administered for IE caused by specific pathogens. Patients who received a combination of antibiotics in each group were excluded from this study. Ampicillin/sulbactam was administered as a 3-g dose every 6 h, as recommended in the treatment guidelines. The dose was adjusted in patients with impaired renal function. Vancomycin was initially administered at a dose of 15–20 mg/kg every 12 h. The dose was adjusted in patients with impaired renal function; in half of the vancomycin group, dose adjustment was guided by therapeutic dose monitoring.The primary outcome was 1-year all-cause mortality. To analyse death outside the hospital and long-term survival, we used mortality data obtained from the Ministry of the Interior and Safety of South Korea, which collects death related information of all Korean citizens. Secondary outcomes included in-hospital all-cause mortality, 28-days all-cause mortality, and overall all-cause mortality. The date of diagnosis of IE was considered the starting point, from which the days until mortality were counted. Nosocomial infection was defined as an infection that occurred after 48 h of hospitalization without any evidence of infection at admission. Charlson Comorbidity Index was calculated at admission for classifying patients according to overall comorbidity . The Seqp < 0.05 in univariate analyses were entered into backward stepwise multivariate Cox model. Hazard ratios and 95% confidence intervals were calculated based on multivariate model. A p-value of <0.05 was considered statistically significant. All statistical analyses were performed using R V.4.0.5 .Differences in patient characteristics and outcomes were assessed between the three groups using the chi-square test for categorical variables and one-way ANOVA or Kruskal-Wallis test for continuous variables. Continuous variables were checked for normal distribution by Shapiro-Wilk test. Chi-square test or Fisher exact test were used to find differences of categorical variables between ampicillin-sulbactam and other antibiotic groups. Survival analysis was performed using Kaplan-Meier curve and log-rank test to estimate long-term outcome. Adjusted Cox regression analyses were performed to assess the risk factors for 1-year mortality of BCNIE and the association between antibiotic therapy and 1-year mortality. Variables with In conclusion, our study did not find a clear difference in treatment outcomes among the various antibiotic therapies used for BCNIE; however it suggested the potential advantage of surgical intervention for the management of this disease. Thus, in terms of global concern and increasing incidence of antimicrobial resistance, it might be reasonable to select ampicillin-sulbactam-based antibiotic therapy and actively consider surgical treatment in BCNIE, especially for community-acquired NVE.


Colchicine may inhibit inflammasome signaling and reduce proinflammatory cytokines, a purported mechanism of COVID-19 pneumonia. The aim of this systematic review and meta-analysis is to report on the state of the current literature on the use of colchicine in COVID-19 and to investigate the reported clinical outcomes in COVID-19 patients by colchicine usage.The literature was searched from January 2019 through January 28, 2021. References were screened to identify studies that reported the effect of colchicine usage on COVID-19 outcomes including mortality, intensive care unit (ICU) admissions, or mechanical ventilation. Studies were meta-analyzed for mortality by the subgroup of trial design  and ICU status. Studies reporting an risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were analyzed separately.Eight studies, reporting on 16,248 patients, were included in this review. The Recovery trial reported equivalent mortality between colchicine and non-colchicine users. Across the other studies, patients who received colchicine had a lower risk of mortality—HR of 0.25  and OR of 0.22 . There was no statistical difference in risk of ICU admissions between patients with COVID-19 who received colchicine and those who did not–OR of 0.26 .Colchicine may reduce the risk of mortality in individuals with COVID-19. Further prospective investigation may further determine the efficacy of colchicine as treatment in COVID-19 patients in various care settings of the disease, including post-hospitalization and long-term care. Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global pandemic. Limited therapies have shown efficacy in the treatment of COVID-19. Remdesivir is recommended for use in hospitalized patients requiring supplemental oxygen, though is not routinely recommended for those who require mechanical ventilation . DexametThe pathophysiology underlying severe COVID-19 pneumonia is an exaggerated inflammatory response, with an overproduction of early response proinflammatory cytokines, including tumor necrosis factor (TNF), IL-6 and IL-1β . In addiSeveral studies have reported on the use of colchicine amongst COVID-19 patients. The COLCORONA investigators reported a randomized controlled trial of 4488 patients non-hospitalized patients with COVID-19, randomly assigning patients to colchicine or placebo for 30 days . In a prThe aim of this systematic review and meta-analysis is to report on the state of the current literature on the use of colchicine for COVID-19, and to investigate the reported clinical outcomes in COVID-19 patients by colchicine usage.researchsquare.com were searched from January 2019 through March 24, 2021. The search strategy is presented in The databases of Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials medRxiv, and Two reviewers  independently assessed articles through level 1 title and abstract screening, and level 2 full-text screening. In the case of discrepancies, a discussion occurred between the two reviewers and consensus was achieved on whether to include or exclude a particular study. If consensus could not be achieved, a third reviewer (RC) was consulted.Articles were eligible for inclusion after level 1 screening if the title and/or abstract mentioned COVID-19 and colchicine. These articles then underwent level 2 screening, at which point the full text was reviewed to identify primary research articles that reported COVID-19 outcomes from a clinical or claims database.Articles were included for quantitative synthesis if they (1) were of observational study design and reported a relative risk measure adjusted for possible confounders, or (2) were of RCT and reported either a relative risk measure or event data, and the article compared colchicine recipients to non-colchicine recipients with respect to the outcomes of mortality, mechanical ventilation, ICU admission, or hospital length of study. Study demographics  were also noted for each included study.As with study screening, this process was done by two reviewers , and a third reviewer (RC) was consulted if consensus could not be achieved.Risk of bias was assessed using tools developed by the Cochrane Bias Methods Group, with the Risk Of Bias In Non-randomized Studies–of Interventions (ROBINS-I) tool used for the observational studies and a revised Cochrane risk of bias tool for randomized trials (RoB 2 tool) used for randomized controlled trials , 24.2 was equal to or greater than 50%, a random-effects DerSimonian-Laird analysis model was applied; otherwise (i.e. when there was heterogeneity of I2 less than 50%), a fixed-effects inverse-variance analysis model was used. A p-value of less than 0.05 was considered statistically significant in the test for overall effect.Studies were meta-analyzed for each outcome and by the subgroups of colchicine use relative to hospitalization , study design , and ICU status (ICU patients and non-ICU patients). Studies were meta-analyzed together according to their relative risk ratio; studies reporting on odds ratio (OR) were meta-analyzed to produce a summary OR, and studies reporting a hazard ratio (HR) were separately meta-analyzed to produce a summary HR. For RCTs which reported exclusively event data, ORs were calculated using the Haldane-Anscombe correction. In the event that the meta-analysis’s heterogeneity of Ip-value of > 0.05 indicated low concern for publication bias. All analyses were conducted using Stata 17.Publication bias was assessed visually, using a funnel plot, and statistically, using Egger’s test. A Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research. This systematic review and meta-analysis did not require an IRB submission as data is all publicly available online.Of 540 records that underwent level 1 screening, 537 were identified through database search and 3 identified through backward reference searching. After removing duplicates, 417 records underwent level 1 screening. Subsequently, 129 articles underwent level 2 screening. Ten studies were assessed for quantitative synthesis, of which 8 reported adjusted relative risk ratios and were included in this systematic review and meta-analysis , 15–21 .et al. reported the effects of colchicine on ICU patients, the other seven studies reported on non-ICU patients. Tardif et al., defined a colchicine user as one who used colchicine after COVID-19 diagnosis but before a COVID-19 hospitalization, while the other seven studies defined colchicine users as ones who used colchicine after a COVID-19 hospitalization.Study demographics are presented in Risk of bias assessment is presented in et al., there is no difference in mortality risk between colchicine users and non-users prior to hospitalization for COVID-19—OR of 0.56 . When colchicine is used after hospitalization and excluding the Recovery trial, patients who received colchicine had a lower risk of mortality—HR of 0.25  and OR of 0.22 . The Recovery trial reports no difference in mortality—OR of 1.02   .Subgroup analyses by ICU status and study design are presented in Two studies reported the risk of ICU admissions among patients with COVID-19 and colchicine use. There was no statistical difference in risk of ICU admissions between patients with COVID-19 who received colchicine and those who did not–OR of 0.26  .et al. reported that among patients diagnosed with COVID-19 who used colchicine before hospitalization, there was no significant difference in risk of mechanical ventilation between patients who received colchicine and those who did not–OR: 0.53 . Deftereos et al. reported that among patients diagnosed with COVID-19 who used colchicine after hospitalization, there was no significant difference in risk of mechanical ventilation between patients who used colchicine and those who did not–OR: 0.90 .Two studies reported on the risk of mechanical ventilation among patients with COVID-19 and colchicine use. Tardif et al., which reported on six studies and 881 patients [We present the first comprehensive systematic review and meta-analysis investigating the effects of colchicine use on COVID-19 patients, meeting the methodological guidance for a high-quality systematic review and meta-analysis as recommended by the MOOSE group (23). Our findings, including eight studies, suggest that among existing studies except for the Recovery trial, patients taking colchicine after COVID-19 diagnosis had a lower risk of mortality in the pooled estimate. With eight studies reporting on 16,248 patients in total, this meta-analysis has greater statistical power than the meta-analysis of Vrachatis patients .et al. [et al. included two observational studies that did not report adjusted OR which were excluded in our analysis [More specifically, this systematic review and meta-analysis differs from the meta-analysis by Vrachatis et al.  in threeet al.  and the analysis , 25. Givet al., in a pre-specified analysis of patients with PCR-proven COVID-19, the colchicine group showed a reduction in the primary outcome which was a composite rate of death or hospitalization compared with placebo—OR = 0.75, 95% CI: 0.57–0.99; p = 0.04 [In the trial by Tardif p = 0.04 . The preet al. found that colchicine is beneficial in non-hospitalized patient in terms of preventing hospitalization or death. Without the Recovery trial, our results suggested that among non-ICU hospitalized patients, colchicine users were at a lower risk of mortality relative to non-colchicine users. Rodriguez-Nava et al., reported that ICU patients had a lower risk of mortality when using colchicine.Given that some studies in this analysis studied hospitalized patients and others studied non-hospitalized patients, it is informative to identify the timing of the exposure of colchicine to patients in relation to the timing of their hospitalization if possible . All stuHowever, the Recovery trial  reports et al’s. study [If there is any solace in these results, it is that colchicine may be beneficial or have a null effect in patients with COVID-19. Given that colchicine is generally a well-tolerated drug, is a relatively inexpensive drug, and, despite known diarrhea rates of 23% in colchicine users , has a gs. study , there iThis study is not without limitations. Intrinsic to meta-analysis study designs, the strength of meta-analysis conclusions is limited to the strength of the input studies and underlying data. This meta-analysis contains a mix of observational and RCT data. To reduce bias in grouping observational and RCT, studies were grouped by trial design when comparing mortality in colchicine and non-colchicine users and only studies reporting adjusted risk estimate were used in observational studies. Additionally, all included studies had some concern for risk of bias. Moreover, this review only contains eight studies, with only two studies examining the risk of ICU admission and two evaluating the risk of mechanical ventilation. Furthermore, the long-term effects of COVID-19 are a significant clinical concern and a major source of disability and health care utilization , 28. FurIn conclusion, our meta-analysis suggests that colchicine may reduce or lead to equivalent risk of mortality in individuals with COVID-19, based on the existing observational studies and trials. Further prospective investigation may further determine the efficacy of colchicine as treatment in COVID-19 patients in various care settings of the disease, including post-hospitalization and long-term care.S1 Checklist(DOC)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S4 Appendix(DOCX)Click here for additional data file.