Does the association between SARS-CoV-2 infection and severe maternal morbidity (SMM), including nonrespiratory complications, vary by viral strain?In this retrospective cohort study of 3129 patients with SARS-CoV-2 infection and 12 504 patients without infection giving birth in a large US health system between March 2020 and January 2022, the risk of SMM associated with SARS-CoV-2 infection was significantly higher during the phase of the pandemic when the Delta variant was predominant (July 2021-November 2021). This association was also noted specifically for both respiratory and nonrespiratory SMM.These findings highlight the importance of the prevention of SARS-CoV-2 infection in pregnant individuals and the consideration of infection as a risk factor for adverse peripartum maternal outcomes. This cohort study evaluates the association of SARS-CoV-2 infection and severe maternal morbidities in patients giving birth during 4 pandemic periods characterized by predominant viral strains. Infection with SARS-CoV-2, which causes COVID-19, is associated with adverse maternal outcomes. While it is known that severity of COVID-19 varies by viral strain, the extent to which this variation is reflected in adverse maternal outcomes, including nonpulmonary maternal outcomes, is not well characterized.To evaluate the associations of SARS-CoV-2 infection with severe maternal morbidities (SMM) in pregnant patients delivering during 4 pandemic periods characterized by predominant viral strains.This retrospective cohort study included patients delivering in a multicenter, geographically diverse US health system between March 2020 and January 2022. Individuals with SARS-CoV-2 infection were propensity-matched with as many as 4 individuals without evidence of infection based on demographic and clinical variables during 4 time periods based on the dominant strain of SARS-CoV-2: March to December 2020 (wild type); January to June 2021 (Alpha [B.1.1.7]); July to November 2021 (Delta [B.1.617.2]); and December 2021 to January 2022 (Omicron [B.1.1.529]). Data were analyzed from October 2021 to June 2022.Positive SARS-CoV-2 nucleic acid amplification test result during the delivery encounter.The primary outcome was any SMM event, as defined by the US Centers for Disease Control and Prevention, during hospitalization for delivery. Secondary outcomes were number of SMM, respiratory SMM, nonrespiratory SMM, and nontransfusion SMM events.P for trend < .001). The findings were similar for respiratory complications, nonrespiratory complications, and nontransfusion outcomes. For example, the risk of nonrespiratory SMM events for patients with vs without SARS-CoV-2 infection were similar for the wild-type strain  and Alpha variant , highest for the Delta variant , and not significantly higher in the Omicron period .Over all time periods, there were 3129 patients with SARS-CoV-2, with a median (IQR) age of 29.1 (24.6-33.2) years. They were propensity matched with a total of 12 504 patients without SARS-CoV-2, with a median (IQR) age of 29.2 (24.7-33.2) years. Patients with SARS-CoV-2 infection had significantly higher rates of SMM events than those without in all time periods, except during Omicron. While the risk of any SMM associated with SARS-CoV-2 infection was increased for the wild-type strain  and Alpha variant , the risk during the Delta period was higher (OR, 7.69 ; This cohort study found that the SARS-CoV-2 Delta variant was associated with higher rates of SMM events compared with other strains. Given the potential of new strains, these findings underscore the importance of preventive measures. Some studies found higher rates of maternal complications, such as caesarian and preterm deliveries,5 while others did not identify an increase in maternal risk.7 As the pandemic evolved, with greater spread and the emergence of SARS-CoV-2 variants, more studies reported an association between SARS-CoV-2 infection and higher rates of poor maternal outcomes, including eclampsia, preeclampsia, HELLP syndrome , sepsis, intensive care unit admission, preterm birth and low birth weight, and, more recently, maternal death or serious morbidity related to hypertensive disorders of pregnancy, postpartum hemorrhage, or infection other than SARS-CoV-2.11Between January 2020 and February 2022, more than 170 000 pregnant people in the US were infected by SARS-CoV-2 and 29 000 pregnant people were hospitalized with COVID-19.12 One study13 from a single hospital found higher COVID-19 caseloads and severity of illness among pregnant people during the Delta surge compared with previous surges. However, this study did not assess adverse maternal outcomes around the time of delivery. Another early study14 at 1 institution presented findings suggesting serious morbidity and adverse perinatal outcomes associated with the Delta variant in pregnancy. In December 2021, Omicron became the predominant strain in the US, and although this strain continued to be responsible for hospitalizations and deaths, disease severity was generally less than the Delta strain.15 Maternal outcomes for people infected with the Omicron variant are not well characterized.The pandemic has been characterized by several waves defined by viral strains that are responsible for the preponderance of infections. In July 2021, the Delta (B.1.617.2) variant of SARS-CoV-2 became the predominant variant in the US.16 To address this question, we studied pregnant patients delivering in a geographically diverse multistate US health system between March 2020 and January 2022.The primary objective of our study is to evaluate the association between SARS-CoV-2 infection and severe maternal morbidities (SMM), as defined by the US Centers for Disease Control and Prevention (CDC), in pregnant patients during pandemic periods when the wild-type strain or Alpha (B.1.1.7), Delta, or Omicron (B.1.1.529) variants of SARS-CoV-2 predominated. The CDC defines SMM as unexpected outcomes of labor and delivery, consisting of 21 health indicators, that result in significant short- or long-term consequences to an individual’s health.STROBE) reporting guideline.This cohort study was deemed exempt from review and informed consent by the Ascension Seton Institutional Review Board under 45 CFR 46.104 of the Common Rule. This study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology , January 2021 to June 2021 (Alpha variant), July 2021 to November 2021 (Delta variant), and December 2021 to January 2022 (Omicron variant).All patients who delivered during the study period in any of 32 hospitals within the health system were candidates for inclusion. Individuals were identified to have a SARS-CoV-2 infection if they had a positive result using polymerase chain reaction nucleic acid amplification testing for SARS-CoV-2 infection during the encounter for delivery. Individuals with a negative test result or for whom test results were not available were categorized as controls. Early in the pandemic, owing to limited testing capacity, only patients with symptoms that would qualify for a person under investigation, including fever, cough, dyspnea, diarrhea, or a close contact with someone with SARS-CoV-2 infection, were tested at admission. Universal testing for all pregnant patients admitted for delivery was initiated in May 2020, during the wild-type strain period. Because of this variation in testing practices across pandemic periods, outcomes were compared in sensitivity analyses between those with confirmed SARS-CoV2 infection and those with a documented negative test result for SARS-CoV2 .SMM outcomes, SARS-CoV-2 infection status, and other patient information were derived from a combination of health system data, including acute care claims data for inpatient encounters and standardized data elements from electronic health records. Race and ethnicity were self-reported for most patients, but the source could not be confirmed for all reviewed records. Race was categorized as Black, White, and other, which included all races other than White or Black, as well as those for whom race was unknown or for whom documentation of race was declined. If race was unknown but ethnicity was Hispanic or Latino, the person was classified as Hispanic or Latino. If ethnicity was unknown, non-Hispanic or Latino ethnicity was assumed. Race and ethnicity were assessed because of potential differential associations with maternal outcomes independent of SARS-CoV-2 infection. Missing demographic data were not altered and are reported as unknown. For each individual SMM, a null value was considered to be a nonevent and not counted in the totals.16 To identify delivery hospitalizations with SMM, the CDC uses administrative hospital discharge data and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis and procedure codes. The CDC’s 2019 list of SMM includes 21 health indicators .16 Secondary outcomes included the number of SMM events, any respiratory SMM , nonrespiratory SMM events, and nontransfusion SMM events.The primary outcome was any SMM event occurring during the hospitalization for delivery. These events are defined by the CDC as including unexpected outcomes of labor and delivery that result in significant short- or long-term consequences to an individual’s health.2 or Fisher exact tests. Age was treated as a continuous variable, presented as median and IQR, and compared using the Wilcoxon rank-sum test. A multivariable logistic regression model with demographic and clinical variables was performed to estimate a propensity score with which individuals with SARS-CoV-2 infection were matched to those without infection. Nearest-neighbor matching was performed with each case matched to a maximum of 4 controls using a caliper of 0.2. Propensity score modeling and matching were performed independently within each of the 4 time frames. Standardized mean differences quantified the quality of the match, with differences less than 10% representing acceptable balance on covariates. Matched data were used to compare the rates of SMM events between those with and without SARS-CoV-2 infection for each variant time frame. A 2-sided P < .05 was designated as statistically significant. All statistical analyses were performed in R statistical software version 4.0.2 . Data were analyzed from October 2021 to June 2022.Categorical variables were summarized as frequencies and percentages, and were compared using χOverall, 3129 patients with SARS-CoV-2 infection, with a median (IQR) age of 29.1 (24.6-33.2) years and 98 325 patients without documented infection delivered at 32 facilities between March 2020 and January 2022  without evidence of infection, with 978 cases and 3906 controls in the wild-type strain period; 744 cases and 2974 controls in the Alpha period; 681 cases and 2724 controls in the Delta period, and 726 cases and 2900 controls in the Omicron period . Among pP for trend < .001). The risk for any SMM associated with the Omicron variant was not statistically significant . Notably, the risk of SMM in the group without evidence of SARS-CoV-2 infection was consistent among the time periods.Patients with SARS-CoV-2 infection had significantly higher rates of any SMM event than those without infection in all time periods, except Omicron , A. RateP for trend < .001). In an analysis restricted only to nonrespiratory SMM, patients with SARS-CoV-2 infection had significantly higher observed rates of nonrespiratory SMM for all variants, except Omicron (P for trend < .001) (P for trend < .001)  , B. In a < .001) , C.In secondary analyses, the control group was restricted only to patients with a documented negative test result for SARS-CoV-2. The characteristics of the propensity-matched population were similar to that of the primary analysis  in pregnant patients with SARS-CoV-2 infection during gestation than in the general population.19 With the potential emergence of future SARS-CoV-2 variants and the magnitude of the risk for adverse maternal outcomes associated with SARS-CoV-2 infection and particularly with the Delta variant, our study underscores the critical importance of promoting prevention strategies to reduce risk to pregnant people at the time of delivery. Several recent studies, as well as recommendations from the CDC and professional organizations, including the American College of Obstetricians and Gynecologists, the Society of Maternal-Fetal Medicine, and the American Academy of Pediatrics, all support the promotion of COVID-19 vaccination in pregnant people and people of childbearing age to reduce risk of adverse outcomes.24 Despite these recommendations, as well as studies showing vaccines are safe in pregnancy, COVID-19 vaccine uptake remains low among pregnant people and people of childbearing age.27 Furthermore, misinformation regarding the vaccine is widespread, including among people who are pregnant or who are planning to get pregnant.28 Our findings underscore the importance of promoting vaccination acceptance and combating misinformation together with other prevention strategies in pregnant individuals. In addition, early diagnosis of infection and prompt therapeutic intervention for SARS-CoV-2 infection with antivirals and monoclonal antibodies may reduce the frequency and severity of maternal morbidities.31Our study adds to previous work by examining and demonstrating the risk of adverse maternal outcomes specifically at the time of labor and delivery and comparison associated with 4 strains of SARS-CoV-2. Previous studies examined the outcomes of COVID-19 in pregnant patients throughout pregnancy.Although this is one of the largest studies investigating the associations of different strains of SAR-CoV2 with SMM in a geographically and demographically diverse population during the pandemic, the results of this study should be interpreted in the context of several limitations. First, we were unable to account for maternal vaccination status owing to inadequate data availability. While this is not relevant to the original period and would only have a modest impact on the Alpha variant period, it would have a greater impact on later periods. In any event, because maternal testing was universal in the later periods, and because vaccination is generally associated with less severe SARS-CoV-2 infection, the differences in outcomes in the later periods relative to the original period associated with infection would, if anything, be biased toward the null. Second, not all patients early in the wild-type strain period were tested for SARS-CoV-2 infection. In periods when universal testing was used, we were unable to differentiate between incidentally discovered SARS-CoV2 infection vs symptomatic COVID-19. In principal analysis, patients who were not tested were assumed to be negative. This raises the question of potential surveillance bias early in the wild-type strain period, when patients with symptoms were more likely to be tested than those without symptoms. However, the results remained consistent even when we removed patients who were not tested for SARS-CoV-2 from the analysis. Third, we were unable to identify patients who had experienced a SARS-CoV-2 infection during their pregnancy and had recovered to the point when testing would not identify an active infection. Thus, it is possible that some of the adverse outcomes in patients without a positive test result could have been attributable to an earlier infection. Again, this issue would bias the results of the study toward the null. Fourth, we did not have sequencing data to identify the strain in individuals with SARS-CoV-2 infection. We used time period as a proxy for the dominant strain of SARS-CoV-2. However, epidemiology data suggest that the selected strains  were dominant and accounted for more than 70% of infections during each of the 4 time periods used. Fifth, because the study is limited to hospitals within a single health system, the results may not reflect outcomes in the broader US population. However, the population of sites and individuals is geographically and demographically diverse.In this cohort study in a large US health system, infection with SARS-CoV-2 at the time of delivery throughout the pandemic was associated with higher rates of SMM; however, this association was particularly strong with the Delta strain. This variable association with viral strain was present both for respiratory and nonrespiratory complications, as well as complications not related to blood transfusion. These findings highlight the importance of SARS-CoV-2 prevention in pregnant patients and consideration of infection as an indicator of high risk in the peripartum period.


Large thrombus burden (LTB) during ST-segment elevation myocardial infarction (STEMI) could translate into worse clinical outcomes. The impact of a LTB in terms of long-term clinical outcomes on different myocardial infarct territories has not yet been fully evaluated. From April 2002 to December 2004, consecutive patients with STEMI undergoing percutaneous coronary intervention with drug eluting stent were evaluated. The study sample was stratified in two groups: anterior STEMI and non-anterior STEMI. LTB was considered as a thrombus larger than or equal to 2-vessel diameters, and small thrombus burden less than 2-vessel diameters. Major adverse cardiac events (MACE) were evaluated at 10-year and survival data were collected up to 15-year. A total of 812 patients were evaluated, 6 patients were excluded due to inadequate angiographic images, 410 (50.9%) had an anterior STEMI and 396 (49.1%) a non-anterior STEMI. Patients with LTB had higher rates of 10-year mortality  and 10-year MACE  in anterior STEMI, but not in non-anterior STEMI . LTB was associated with increased 30-day mortality  and 30-day MACE  in anterior STEMI, but not in non-anterior STEMI . Beyond 30-day, LTB had no impact on mortality and MACE in both groups. In anterior STEMI, LTB is associated with worse long-term clinical outcomes, this effect was driven by early events.The online version contains supplementary material available at 10.1007/s11239-021-02603-3. Large thrombus burden has a significant impact on mortality and MACE at 10 years in patients with anterior STEMI, but not in patients with non anterior STEMI.The impact of thrombus burden is mainly driven by early events.The reclassification of the thrombus burden after wire crossing in the occluded infarct related artery (G5) was applicable in almost every lesion, 99% of the cases.More than two thirds of the thrombotic occlusions, initially evaluated as large thrombus burden were actually caused by small thrombus.The reclassification of G5 might improve quantitative thrombus estimation.Primary percutaneous coronary intervention (PCI) represents the gold standard therapy for coronary revascularization during ST-segment elevation myocardial infarction (STEMI) and a timely reperfusion strongly correlates with clinical outcomes . HoweverThe presence of large thrombus burden (LTB) in the infarct related artery (IRA) might increase the risk of distal embolization, microvascular obstruction, and no-reflow phenomenon leading to contractile dysfunction and irreversible myocardial damage –11.Thrombus burden is classified by visual angiographic assessment in LTB defined as thrombus equal or greater than two vessel diameters and in small thrombus burden (STB) less than two vessel diameters . In casePrevious studies demonstrated that LTB is an independent predictor of early mortality, repeat myocardial infarction, and IRA revascularizations , 12.In patients with STEMI, the anterior localization of the infarction is often associated with greater myocardial dysfunction, heart failure and increased mortality, mostly due to the larger myocardial territory supplied by the left anterior descending artery (LAD) –18.Hypothetically, the embolization of a large amount of thrombotic debris in the territory supplied by LAD might lead to greater left ventricular dysfunction and worst prognosis, demanding more effective interventions.The impact of LTB on clinical outcomes in different myocardial infarct territories has not yet been evaluated. Therefore, the purpose of the present study was to investigate the impact of the thrombus burden on very long-term clinical outcome in anterior and in non-anterior STEMI.From April 2002 to December 2004, all consecutive patients with STEMI undergoing PCI in the Erasmus University Medical Center (EMC), Rotterdam, the Netherlands, were evaluated. Patients with STEMI treated with PCI and drug eluting stent (DES) within 12 h after the onset of myocardial ischemia symptoms were included in the analysis. Patients with non-quantifiable thrombus burden were excluded.Demographic and clinical characteristics were assessed from the hospital database. All patients received a loading dose of aspirin and clopidogrel before the PCI procedure that was performed according to standard clinical practice. Thrombus aspiration and glycoprotein IIb/IIIa inhibitors (GPIs) treatment were at the operator’s discretion.On the basis of IRA occlusion, the population was stratified into two groups: anterior STEMI due to the LAD occlusion and non-anterior STEMI due to non-LAD occlusion.The Medical Ethics Committee of the EMC reviewed the study protocol and waived the need for additional informed consent because of the non-interventional character of this observational study using anonymous data collection. The investigation conforms to the principles outlined in the Declaration of Helsinki.The angiographic data were revised by two experienced interventional cardiologists as described previously .Intracoronary thrombus at baseline was angiographically identified and scored according to Thrombolysis in Myocardial Infarction (TIMI) thrombus grade : grade 0No-reflow was defined as reduced anterograde flow (TIMI flow ≤ grade 2) in the absence of occlusion at the treatment site . Distal The municipal civil registry in the Netherlands was consulted for the survival status of all patients.Information on hospitalization and cardiovascular events were obtained through health questionnaires. If necessary, referring cardiologists and general practitioners were contacted for additional data. In case of re-hospitalization medical records or discharge letters from other hospitals were collected. Clinical follow-up was performed at 10 years and survival data were collected at 15 years.Major adverse cardiac event (MACE) was defined as the composite of all-cause mortality, repeat myocardial infarction (MI), and target vessel revascularization (TVR). TVR was defined as any repeat percutaneous intervention or coronary artery bypass grafting of any segment of the infarct related artery.t-test or Mann-Whitney U test as appropriate. Categorical variables expressed as numbers and percentages were compared by Pearson chi-square analysis or Fisher’s exact test, as appropriate.Continuous descriptive variables were expressed as mean ± standard deviation (SD) or median and interquartile range (IQR: 25th -75th percentile), and were compared using the Student’s Kaplan-Meier curves were generated for cumulative MACE and mortality events rates, the Cox proportional-hazard regression was used to establish the differences between groups.The univariate analysis was performed using the Cox proportional hazards regression, with all the following variables: age, gender, diabetes mellitus, arterial hypertension, hypercholesterolemia, smoking, family history of coronary artery disease, previous myocardial infarction, previous PCI, primary PCI, stent thrombosis at the index procedure, cardiogenic shock, multivessel disease, multivessel PCI, baseline TIMI flow grade 0-1, glycoprotein IIb/IIIa inhibitors, bifurcation stenting, direct stenting, thrombectomy, final TIMI flow grade 3, no-reflow, distal embolization. Variables that were significant in univariate analysis at a level of p <0.10 were assessed in the multivariate Cox model. LTB was forced into the model to estimate its independent effect along with the other predictors of clinical outcomes.Landmark analysis for mortality and MACE was performed with a 30-day landmark time point.A 2-tailed p value of <0.05 was considered statistically significant and 95% confidence intervals (CI) were presented for all hazard ratio (HR). Statistical analyses were performed using the SPSS statistical software package for Windows, version 25.0 .Between April 2002 and December 2004, 812 consecutive patients with STEMI undergoing percutaneous revascularization with DES were evaluated. Six patients were excluded due to the inadequate angiographic images that made thrombus burden non-quantifiable, 806 patients were included in the analysis, 410 (50.9%) had an anterior STEMI and 396 (49.1%) had a non-anterior STEMI.The baseline and angiographic characteristics of anterior and non-anterior STEMI according to thrombus burden are summarized in Table Higher peak of CK-MB, bifurcation stenting and distal embolization were higher in anterior STEMI than in non-anterior STEMI.Multivessel disease and direct stenting were higher in non-anterior STEMI than in anterior STEMI.Out of the 806 patients more than half  presented an occluded IRA (G5) Fig. . ReclassCompleteness of follow-up information at 10 years was obtained in 797 (98.9%) patients and survival data were recorded up to 15 years.At 10-year, clinical outcomes were similar between patients with anterior and non-anterior STEMI in terms of mortality , MI , TVR  and overall MACE .At 15-year, mortality rate was 34.8% (n = 277) without difference between anterior and non-anterior STEMI .In anterior STEMI, before G5 reclassification, 10-year mortality rate was higher in LTB than in STB , and 10-year MACE rate was similar between the two groups     in the anterior STEMI group, but no significant differences were found in the non-anterior STEMI group  . Beyond 30-day, morality rate was similar between the two groups  . Thereafter, MACE rates were comparable between patients with LTB and STB   and beyond 30-day   and neither after 30 days   LTB had a significant impact on mortality and MACE at 10 years in the anterior STEMI group, but not in the non-anterior STEMI group, (2) the effect of LTB was mainly driven by early events (≤30 days), after 30 days the thrombus burden had a limited impact on clinical outcomes, and (3) the reclassification of G5 might improve quantitative thrombus estimation, when thrombus burden was reclassified, differences in MACE rate became evident between the groups.An adequate evaluation of the real amount of the thrombus burden is essential to identify the lesions that might be at high risk of distal embolization, in particular the total occlusion of the infarct related artery, namely thrombus grade G5, reflects only the state of the flow rather than the real amount of the thrombus.In our analysis the reclassification of G5 after wire or small balloon passage was applicable in almost every (99.6%) lesion. More than two thirds (67.5%) of the thrombotic occlusions (G5), initially evaluated as large thrombus burden were actually caused by small thrombus.In anterior STEMI, mortality and MACE rates were higher in patients with LTB compared with those with STB; conversely, the amount of thrombus had a negligible effect on clinical outcomes in non-anterior STEMI.These findings might be related to the higher myocardial mass perfused by the LAD compared to other myocardial regions . UsuallyOn the other hand, in non-anterior infarctions, distal embolization might play a less relevant role on infarct size given the smaller area perfused by the right coronary artery or by the circumflex.The present study is the first reporting very long term clinical outcomes in patients with acute myocardial infarction stratified per thrombus burden and infarct localization. In our analysis, the impact of thrombus burden in anterior STEMI was mainly driven by the early events and beyond 30 days, up to 10-year, thrombus burden was poorly associated with mortality and MACE.Given our results, patients presenting with anterior STEMI and large thrombus burden may represent a sub-population at high risk of distal embolization and higher short-term event rate, which might benefit by additional periprocedural therapeutic strategies.Current European and American guidelines on myocardial revascularization in patients with STEMI suggest glycoprotein IIb/IIIa antagonist and/or thrombectomy as for bail-out scenarios including high thrombus burden or thrombotic complications, although specific studies are lacking , 24, 25.In our analysis a large thrombus burden was associated with increased mortality and MACE mainly during the first month after primary PCI for anterior infarction, suggesting that a highly thrombotic milieu might affect in particular procedural complication and early events. In this scenario not only thrombus aspiration but also additional pharmacologic strategies to achieve rapid platelet inhibition could be considered to minimize the negative impact of large thrombus burden in anterior STEMI –34.This is a single center, observational, retrospective study with its inherent limitations of selection bias and missing data. A small percentage of the population underwent rescue PCI and thrombus burden modification cannot be excluded. Only first-generation DES were implanted. Finally antiplatelet therapy was prescribed for at least 6 months according to recommendations at that time.Further technologies and development of thrombus aspiration devices are warranted to improve the effectiveness of thrombus removal without increase the risk of stroke; thrombectomy may particularly benefit patients with a large thrombotic burden.Large thrombus burden is associated with higher mortality and MACE rate in patients with anterior STEMI but not in non-anterior STEMI. The impact of a large thrombus burden on clinical outcomes is mainly associated with early events.Supplementary material 1 (DOCX 27.9 kb)Below is the link to the electronic supplementary material.


Rising caesarean-section rates worldwide are driven by non-medically indicated caesarean-sections. A systematic review concluded that the ten-group classification system (Robson) is the most appropriate for assessing drivers of caesarean deliveries. Evidence on the drivers of caesarean-section rates from conflict-affected settings is scarce. This study examines caesareans-section rates among Palestinian refugees by seven-group classification, compares to WHO guidelines, and to rates in the host settings, and estimates the costs of high rates.Electronic medical records of 290,047 Palestinian refugee women using UNRWA’s  antenatal service from 2017–2020 in five settings  were used. We modified Robson criteria to compare rates within each group with WHO guidelines. The host setting data were extracted from publicly available reports. Data on costs came from UNRWA’s accounts.Palestinian refugees in Gaza had the lowest caesarean-section rates (22%), followed by those residing in Jordan (28%), West Bank (30%), Lebanon (50%) and Syria (64%). The seven groups caesarean section classification showed women with previous caesarean-sections contributed the most to overall rates. Caesarean-section rates were substantially higher than the WHO guidelines, and excess caesarean-sections (2017–2020) were modelled to cost up to 6.8 million USD. We documented a steady increase in caesarean-section rates in all five settings for refugee and host communities; refugee rates paralleled or were below those in their host country.Caesarean-section rates exceed recommended guidance within most groups. The high rates in the nulliparous groups will drive future increases as they become multiparous women with a previous caesarean-section and in turn, face high caesarean rates. Our analysis helps suggest targeted and tailored strategies to reduce caesarean-section rates in priority groups (among low-risk women) organized by those aimed at national governments, and UNRWA, and those aimed at health-care providers.The online version contains supplementary material available at 10.1186/s12884-022-05264-z. Medically-indicated caesarean-section is effective in reducing maternal and neonatal mortality and morbidity and stillbirths. However, the World Health Organization (WHO) suggests rates above 10% do not confer additional maternal or perinatal benefits , while aNon-medically indicated caesarean-sections pose unnecessary risks to mothers and children, and add financial costs. Maternal risks include haemorrhage, infections, anaesthetic and thromboembolic events, and surgical/urological complications, e.g. fistula , 8. LongLimiting unnecessary caesarean-section requires understanding its drivers. WHO recommends the Robson classification to monitor and prioritize where caesarean-section rates should be reduced . Robson Caesarean-section rates among Palestinian refugees have doubled from 15 to 31% between 2006–2020 , 19. RefThis study examines and contextualizes caesarean-section rates among Palestinian refugees residing in the five settings where UNRWA operates, from 2017 to 2020. We examined caesareans-section rates among Palestinian refugees by using a seven groups caesarean section classification modelled on the Robson classification, compared these to WHO guidelines and to rates in the host settings, and estimated the costs of rates above the guidelines.We relied UNRWA electronic medical records (EMR) and cost data, and on desk reviews of annual health reports., 49% in West Bank, 73% in Gaza, 34% in Syria; it is difficult to estimate in Lebanon [The percentage of pregnant Palestinian refugees using UNRWA’s antenatal care services is estimated at around 35% in Jordan Lebanon . In SyriUNRWA’s EMR is a web-based patient-centred digital system capturing every primary healthcare clinic visit recorded by the doctor, nurse, or midwife caring for women. It includes contemporaneous modules on antenatal care, and antenatal referrals, and records pregnancy outcomes retrospectively during postnatal care, the child’s first vaccination visit, or by telephone follow-up. In 2017, the EMR system was updated to record information on the mother , obstetric history , and more detailed current pregnancy outcomes .We extracted anonymized electronic medical records data for pregnancies ending between January 1, 2017, to December 31, 2020. Data analysis was performed in accordance with the ethics guidelines and regulations. UNRWA is the main custodian of the electronic health system and maintains the system following ethical, legal privacy and confidentiality requirements. We obtained ethics approval from UNRWA’s research review board and the London School of Health & Tropical Medicine Research Ethics Committee  (Date: 12 November 2020). Participant consent was not required as the study used de-identified registry based secondary data. As long as the work does not violate the rights of individuals and does not include identifiable information, UNRWA permit researchers to access EMR without obtaining prior consent from participants to pursue research for the common good of Palestinian refugees. Informed consent was waived by UNRWA’s research review board.UNRWA’s EMR dataset included some variables required for the Robson classification: parity (nulliparous (nullip)/multiparous (multip)), previous caesarean-section (yes/no), number of fetuses 1/2 +), gestational age (preterm (defined as less than 37 weeks completed)/term) and fetal lie/presentation   in their capacity as hospitalisation consultant and Director of Health Department at UNRWA.We calculated frequencies and cross-tabulations to assess data quality and investigated missing data. Because the EMR reports women’s current age and parity status, we adjusted these to reflect the values when the index delivery occurred. To assess external validity, we compared our data to population surveys and national statistics.We restricted the analysis to women who delivered a live birth at any gestation or a stillbirth at 28 completed weeks of gestation or beyond  . Data coTo understand the financial impact of the caesarean section performed, we costed all deliveries as if they were performed in UNRWA contracted hospitals.From January 1, 2017, to December 31, 2020, UNRWA EMR included data on 294,184 live births and 1,401 stillbirths which occurred in a total of 291,704 delivery events. Missing data ranged from 0.2% in Gaza to 1.5% in Syria; the final analysis data included 290,047 births (99.5%).Most women who delivered were 20–29 years old, with Syria and Jordan having the highest prevalence of women under 20 years of age Table . Gaza coCaesarean-section rates were highest for refugees in Syria (64%), followed by Lebanon (50%), West Bank (30%), and Jordan (28%) Fig. . Gaza haBetween 2017 and 2020, caesarean-section rates increased by 1% in the West Bank 3% in Jordan, Syria, and Gaza, and 5% in Lebanon, with average annual rates of increase ranging from 0.42% to 1.94%. The largest increase in caesarean-section rates was among nulliparous women   was the highest contributor to the overall caesarean-section rate Fig. . A sub-aCaesarean-section rates for group groups 3 + 4  also exceeded guidance of below 6%  evidence for the need to add missing data elements in UNRWA EMR to be able to implement the ten group classification system (Robson) (2) high and increasing caesarean section rates (3) caesarean section rates within most groups exceeding guidelines, (4) a built-in momentum caused by high caesarean section rates among nulliparous women, who will likely have subsequent caesareans, (5) a powerful correlation with host country caesarean section rates, which are also increasing, (6) a considerable financial cost associated with potentially unindicated caesarean section, and (7) sub-optimal clinical management.This study showcases the need to ensure routine EMR capture all the data necessary to fully implement the ten-groups classification system (Robson) as recommended by WHO. Our study was limited by the absence of data elements on onset of labour (spontaneous/induced) or pre-labour caesarean-section and the type of fetal abnormal lie/malpresentation type and so could not benefit from the full extent of Robson group classification, size of the group  and the WHO recommendation for monitoring rates. A direct consequence of our study, is that UNRWA already added the types of presentation and onset of labour variables to its EMR, an example of collaborative research informing practice. A remaining concern however is whether this data will be captured accurately by the recently delivered women’s’ reports. This is a challenge in EMR that are collected in primary health care facilities on births which occurred elsewhere. One suggestion is that hospitals would provide all ten-group classification systems data elements in the discharge summary sheets linked to reimbursement. The EMR should also capture the number of previous cesarean-section to subdivide analysis in group 5 into group 5.1 (one previous caesarean section) and group 5.2 (the two or more previous caesarean section).Caesarean-section rates in all five settings 22%-64%) were higher than the rates associated with improvements in maternal or neonatal outcomes or stillbirths (9–19%) , 4, sugg% were hiGroups with low indication for caesarean-section, specifically the nulliparous women group (1 + 2) and the multiparous women without a previous caesarean-section group (3 + 4), had rates that were higher than WHO guidelines.The rapid rise in caesarean-section rates over time stems partly from the increase in rates of first caesarean-section among the nulliparous group (group 1 + 2), combined with high fertility, whereby these women go on to have multiple subsequent births. Palestinian refugees have relatively high total fertility rates, around 3.6 births per women in West Bank and Gaza in 2020, 3.3 in Jordan in 2010, 2.7 in Lebanon in 2017, 2.5 in Syria in 2011 . ReflectThe findings from previous studies in Lebanon and Gaza using Robson to classify caesarean-section, are comparable to our results , 33. HowIn the Palestinian refugee context, there is an urgent need to develop strategies targeting low-risk women to optimise vaginal delivery and limit an even more rapid rise in caesarean-section rates, as well as a need to improve quality of care. We use the framework of Betran and colleagues, which identifies interventions and strategies at different levels to discuss potential approaches: namely those linked to national governments and health-care organizations and those linked to health professionals .The high rates and increasing trends in caesarean-section seen in the refugee population do not occur in a vacuum – rather they reflect rates and trends in the national host populations. In West Bank and Gaza, rates among Palestinian refugees and non-refugees are comparable, suggesting there are not major differences in these populations. In Jordan, Lebanon and Syria, the lower rates seen among refugees compared to nationals probably reflect the lower socio-economic status and greater marginalization of refugees, or possibly the rates in the hospitals which UNRWA contracts out.The high and increasing national trends in all five settings also reflect the structure of national health systems. There are low and declining percentages of births attended by midwives. For example, 23.8% of deliveries in Jordan in the 2012 DHS were with midwives, declining to 10.6% in the 2017–18 DHS. The most recent survey data suggest births attended by doctors (largely obstetricians) are 89.1% in Jordan (2017–18), 86.7% in Lebanon (2011), around 80% in Syria (2009 pre-conflict), 70.8% in West Bank (2019–20) and 87.5% in Gaza (2019–20) , 34–36. Health systems in the five settings also have substantial and growing doctor-led private sectors (33.4% Jordan (2017–18), 29.1% Lebanon (2011), 46.3% Syria (2009), 46.3% West Bank (2019–20) and 15.7% Gaza (2019–20)) , 34–36.PCosts associated with unindicated caesarean sections are substantial, particularly in the context of large and ever-growing numbers of refugees and donor fatigue. Unnecessary costs also burden national governments and women and their families, irrespective of refugee/national status.Our results highlight the need to intervene with a unified national effort/policy to decrease caesarean-section for both refugees and women in the national host settings, particularly where donors do not fund their own services, but rather contract them out to national providers. Refugee agencies, namely UNRWA and UNHCR, may also have opportunities to use their financial clout in contracting and negotiating with hospitals. Strategies proposed in the literature at national level include removing perverse financial incentives or changing the percentage coverage of caesarean-sections to avoid privileging these over vaginal births .In addition to the excessive rates within most of the categories which were discussed above, we also found evidence of likely suboptimal clinical decisions by health-care providers, including high rates of caesarean-section among stillbirths and low rates of vaginal birth after caesarean (VBAC).There were high, and increasing, caesarean-section rates among stillbirths (19%-56%). This is higher than rates observed in some high income countries (United State of America (15% in 2014)) and low middle income countries (7% in 2015) , 40. TimTrial of labour after caesarean (TOLAC) and VBAC are uncommon among Palestinian refugees and in the host countries, where “once a caesarean always a caesarean”, is embraced. In our study, 3.2%-30.4% of multiparous women with previous caesarean section had a vaginal birth, and VBAC was particularly low in Lebanon (3.2%) and Syria (5.9%). Some of the benefits of VBAC documented included lower rates of maternal morbidity and mortality and shorter recovery compared to repeated caesarean-sections . RepeateBoth aspects of suboptimal care require support to health providers to improve clinical management. Currently recommended interventions include: educational training, exploring improving adherence to evidence-based practices, caesarean-section decision second opinions policies, clinical audit, and feedback . In termThe literature also suggests provider feedback, showcasing caesarean-section rates using Robson groups in a standardised, and action-oriented manner helps health professional staff see their institutional rates and could also be used as an audit tool . FacilitThe conceptual framework we used assessed drivers and interventions at the community/family/woman level and gave options to target women with information to address concerns about safety, misinformation, or mode of delivery choices. Our study did not gather evidence from women or communities, but there is no evidence that substantial proportions of refugee women are requesting unnecessary caesarean-sections; moreover, women are at a relative disadvantage in the power dynamics of decision making vis-à-vis health providers . A recomDespite most Robson categories having excessive rates, we were surprised to find caesarean-section rates in the malpresentation groups were lower than the Robson guideline. This might be due to misclassification of malpresentation which was captured at the last antenatal visit not labour, or because of our merging of transverse lie with breech.The most successful caesarean-section reduction strategies are multi-faceted. We show that Palestinian refugees caesarean-section rates in five settings were higher than the recommended levels in the group where caesarean-section is unindicated. The analysis indicates the need to collect further information on malpresentation and induction to conduct the 10 groups caesarean classifications (Robson). Our analysis suggests areas where targeted and tailored strategies can be applied to reduce caesarean-section rates in priority groups (among low-risk women) organized by those aimed at national governments, and UNRWA, and those aimed at health-care providers.OC and AS conceived the study. GP, GB, HA extracted the data. ZJ and HA cleaned the data. ZJ and GP analysed the data, with guidance from OC. ZJ, GP, OC wrote the first draft of the manuscript. LTD supported in interpreting the findings and writing the analysis. All authors read and approved the final version.Additional file 1.


Current guidelines recommend systemic thrombolysis as the first-line reperfusion treatment for patients with high-risk pulmonary embolism (PE) who present with cardiogenic shock but do not require venoarterial extracorporeal membrane oxygenation (VA-ECMO). However, little is known about the optimal reperfusion treatment in high-risk PE patients requiring VA-ECMO. We aimed to evaluate whether systemic thrombolysis improved high-risk PE patients’ outcomes who received VA-ECMO.This was a retrospective cohort study using the Japanese Diagnosis Procedure Combination inpatient database from July 2010 to March 2021. We identified patients who were diagnosed with PE and received VA-ECMO on the day of admission. Patients who received systemic thrombolysis with monteplase or urokinase within two days of initiating VA-ECMO were defined as the thrombolysis group and the remaining patients as the control group. The primary outcome was in-hospital mortality and secondary outcomes were favorable neurological outcomes, length of hospital stay, VA-ECMO duration, total hospitalization cost, major bleeding, and blood transfusion volume. Propensity-score inverse probability of treatment weighting (IPTW) was performed to compare the outcomes between the groups.Of 1220 eligible patients, 432 (35%) received systemic thrombolysis within two days of initiating VA-ECMO. Among the unweighted cohort, patients in the thrombolysis group were less likely to have poor consciousness at admission, out-of-hospital cardiac arrest, and left heart catheterization. After IPTW, the patient characteristics were well-balanced between the two groups The crude in-hospital mortality was 52% in the thrombolysis group and 61% in the control group. After IPTW, in-hospital mortality did not differ significantly between the two groups . There were also no significant differences in the secondary outcomes. Sensitivity analyses showed a significant difference in major bleeding between the monteplase and control groups , excluding patients who received urokinase. There were no significant differences in the other sensitivity and subgroup analyses except for the total hospitalization cost.Systemic thrombolysis was not associated with reduced in-hospital mortality or increased major bleeding in the high-risk PE patients receiving VA-ECMO. However, systemic thrombolysis with monteplase was associated with increased major bleeding.The online version contains supplementary material available at 10.1186/s40560-023-00651-w. Acute pulmonary embolism (PE) is the most serious clinical manifestation of venous thromboembolism and is associated with substantial morbidity and mortality , 2. The Current guidelines recommend systemic thrombolysis as the first-line reperfusion treatment for patients with high-risk PE . HoweverThe present study, therefore, aimed to evaluate the effect of systemic thrombolysis on in-hospital mortality and other clinical outcomes including the neurologic outcomes, hospitalization cost, and bleeding events in high-risk PE patients who received VA-ECMO, using a nationwide inpatient database in Japan.This was a retrospective cohort study using an inpatient administrative database, and the study conformed to the RECORD statement reporting guidelines . This stInternational Classification of Diseases, 10th Revision (ICD-10) codes, daily procedures recorded using Japanese medical procedure codes, daily drug administration, and discharge status [We used the Japanese Diagnosis Procedure Combination inpatient database, which contains administrative claims data and discharge abstracts from more than 1500 acute care hospitals and covers approximately 90% of all tertiary emergency hospitals in Japan [e status .Using the Japanese Diagnosis Procedure Combination inpatient database from July 2010 to March 2021, which was the maximum period available at that time, we identified hospitalized patients with the primary diagnosis of PE (ICD-10 code: I26) and who received VA-ECMO on the day of admission. We did not include patients with a suspected diagnosis of PE and patients who developed PE as a complication after hospitalization. We excluded patients who received surgical embolectomy without systemic thrombolysis within two days of admission.Patients who received systemic thrombolysis within two days of initiating VA-ECMO were defined as the thrombolysis group because the current guidelines suggest that systemic thrombolysis is most effective when initiated within 48 h of the symptom onset , and theCovariates included age, sex, smoking history, body mass index at admission, Japan Coma Scale (JCS) at admission , out-of-The primary outcome was in-hospital mortality. The secondary outcomes were favorable neurological outcomes, length of hospital stay, VA-ECMO duration, total hospitalization cost, major bleeding, and blood transfusion volume. The favorable neurological outcomes were defined as patients with a JCS of 0  or 1–3 (dizziness) at discharge. A score of 0 or 1–3 under the JCS is roughly synonymous with a Cerebral Performance Category (CPC) score of 1 or 2 , 12. TheWe used the inverse probability of treatment weighting (IPTW) by propensity scores to compare the outcomes between the thrombolysis and control groups , 16. We p < 0.05 as statistically significant. All analyses were performed using STATA/SE 17.0 software (StataCorp).Continuous variables were presented as the mean and standard deviation (SD), and categorical variables were presented as the number and percentage. We considered all reported p-values as two-sided and a We assumed that extracorporeal CPR and OHCA had a substantial impact on in-hospital mortality. Therefore, we tested the potential for effect modification of systemic thrombolysis in combination with VA-ECMO on in-hospital mortality as well as the secondary outcomes, depending on whether the patients received CPR on the day of admission or had OHCA. We performed these subgroup analyses among the weighted cohort created in the main analysis.We performed two sensitivity analyses. First, monteplase is a third-generation thrombolytic agent with a longer half-life, higher thrombus sensitivity, and more rapid lysis . TherefoDuring the study period, we identified 1220 eligible patients  in high-risk PE patients who received VA-ECMO. These findings were consistent in the subgroup analyses in the patients with and without CPR or OHCA on the day of admission. However, in the sensitivity analyses, systemic thrombolysis with monteplase was associated with increased major bleeding.n = 2197/1,172,354), while it was applied to 1.5% of hospitalized patients with the primary diagnosis of PE  in the present study. This may be partly due to the differences in the study population, study periods (2005–2018 vs. 2010–2021), and national health insurance system [Unlike our results, a previous study using a nationwide inpatient database in Germany included 2197 high-risk PE patients with VA-ECMO and showed that thrombolysis in combination with VA-ECMO was associated with a lower risk of in-hospital mortality . In the previous study, only age, sex, and comorbidities were adjusted [VA-ECMO alone restores hemodynamics with right ventricular unloading and adequate tissue oxygenation . During The present study had several strengths. First, the present study was based on one of the largest databases, which covered approximately 90% of all tertiary emergency hospitals in Japan. Second, the present study focused not only on the qualitative assessment of the presence or absence of major bleeding but also on the quantitative assessment of blood transfusion volume.The present study had several limitations. First, the decision on whether to use systemic thrombolysis was at the individual clinician’s discretion due to the nature of the present study using the observational database, which led to confounding by indication. We attempted to control for this confounding by indication using the IPTW. However, we were unable to control for any possible unmeasured variables, such as vital signs or laboratory data. Second, the present study was unable to identify whether patients received VA-ECMO after failing systemic thrombolysis or whether they initially received VA-ECMO and then systemic thrombolysis within two days of admission. Third, the incidence of major bleeding events in the present study was considerably lower than in the previous German study   and otheThe present study showed that the use of systemic thrombolysis was not associated with reduced in-hospital mortality as well as increased major bleeding in high-risk PE patients who received VA-ECMO. However, systemic thrombolysis with monteplase was associated with increased major bleeding.Additional file 1: Fig. S1. Distribution of the propensity scores in the thrombolysis and control groups in the unweighted cohort. Fig. S2. Distribution of the propensity scores in the thrombolysis and control groups in the weighted cohort by inverse probability of treatment weighting analyses. Table S1. The JCS scoring and conversion methods from the JCS to the GCS. Table S2. Results of the subgroup analyses by OHCA in the weighted cohort. Table S3. Results of the sensitive analyses after excluding the patients in the control group who received systemic thrombolysis after the third day of initiating VA-ECMO.


Diabetes mellitus is a well-recognized contributor to increased COVID-19 severity. Endothelial dysfunction has been implicated in the pathogenesis of COVID-19, while thrombocytopenia has been identified as a potential risk factor for severe COVID-19. In this study, we evaluated the combined effect of thrombocytopenia and other markers of endothelial dysfunction on disease outcomes in patients with type 2 diabetes and active COVID-19 infection. Our aim was to risk stratify patients with COVID-19 and type 2 diabetes mellitus, which can help identify patients with high-risk features who will benefit the most from hospital admission and a high level of care. This cross-sectional study was performed after reviewing secondary data of 932 patients with COVID-19 and type 2 diabetes mellitus in the outpatient and inpatient settings across Qatar between March 1, 2020 and May 7, 2020. Univariate and multivariate analyses, with adjustment for low platelet counts, were performed for the following variables: age, hemoglobin, white blood cells (WBC), lymphocytes, monocytes, eosinophils, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, ferritin, D-dimer, and interleukin 6. Increasing age was associated with an increased risk for death and/or intensive care unit admission in diabetic patients with COVID-19 who have low platelet counts. These findings support the evidence found in the literature and give special attention to COVID-19 patients with low platelet counts and diabetes mellites. These results can guide physicians in making clinical decisions regarding hospital admission and escalation of care during follow-up in this population of patients. Thrombosis and endothelial dysfunction are well-known pathways contributing to clinical deterioration in COVID-19 patients. In a case series from New York, one-third of COVID-19 patients with electrocardiographic signs of active ischemia showed non-obstructive coronary artery disease upon further evaluation, suggesting that microvascular dysfunction could be a likely cause of ischemia. In severe COVID-19 patients, markers of endothelial and platelet activation are increased compared to non-severe COVID-19 patients. Extensive microthrombosis promoted and aggravated by endothelial dysfunction could explain the profound D-dimer elevation and thrombocytopenia in severe COVID-19. Infection of endothelial cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in endothelial activation and dysfunction. These result in elevated levels of pro-inflammatory cytokines such as interleukin-6 (IL-6). Higher levels of acute phase reactants  are also associated with COVID-19 infection. Serum ferritin levels were found to be an independent risk factor for severe COVID-19 infection.Endothelial dysfunction, widespread inflammatory response, thrombopathy, and microvascular occlusion are among the proposed pathophysiological components of severe COVID-19 infection. Diabetes mellitus is one of the well-recognized comorbidities that lead to adverse clinical outcomes in patients with COVID-19.Endothelial dysfunction is also a common feature of the key comorbidities that increase the risk of severe COVID-19, such as hypertension, obesity, diabetes mellitus, coronary artery disease, and heart failure. The hypothesis of the combined effect of thrombocytopenia and markers of endothelial dysfunction and inflammation on the clinical outcomes of type 2 diabetic patients with COVID-19 remained unexplored till now. Examination of these data will provide clinical evidence for the multiplicative effects of these factors resulting in adverse outcomes in severe COVID-19. Such evidence will help risk stratify type 2 diabetes patients more likely to develop COVID-19 complications. This approach can identify patients more likely to benefit from direct interventions and prioritize hospitalization or escalation of care in patients with adverse laboratory features.The effects of immune and non-immune thrombocytopenia in patients with COVID-19 have been extensively studied in the general population and found to result in adverse outcomes.This is a retrospective cross-sectional study design that reviewed the secondary data of 932 type 2 diabetic patients. They were managed as COVID-19 cases in the outpatient or inpatient settings in the state of Qatar between 1/3/2020 and 7/5/2020. The study was conducted after receiving relevant approval from the medical research center. The sample size was calculated to give enough power to the study to minimize type 1 and type 2 errors. The primary study outcome was the composite of death and/or ICU admission in the study population.Relevant socio-demographic and laboratory parameters were abstracted from an online patient information management system (Cerner) into a Microsoft Excel data collection spreadsheet. Patients were eligible for enrollment in this study if they were over 18 years old with type 2 diabetes mellitus and a confirmed diagnosis of COVID-19 . Data extracted included age, sex, complete blood count, coagulation profile, liver function tests (LFTs), D-dimer, ferritin, and IL-6. Patient outcomes after COVID-19 diagnosis, whether discharged without ICU admission, needed ICU admission, or died, were recorded. Patients were managed according to local COVID-19 guidelines for inpatients or outpatients; therefore, not all the parameters of interest in our study were available for each patient. Platelet count was subcategorized into three categories according to platelet count percentile among the study population. The first category was defined as patients with platelet counts < 185 cells/μl; the second category was patients with platelet counts between 185–232 cells/μl; and the third category was patients with platelet counts between 233–293 cells/μl. A univariate analysis was conducted on the following variables: age, hemoglobin, white blood cells (WBC), lymphocytes, monocytes, eosinophil, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), D-dimer, ferritin, and IL-6. Multivariate analysis, which was adjusted for patients with a lower percentile platelet count, was conducted on the variables which showed statistical significance in the univariate analysis, including age, chronic comorbidities, WBC, lymphocytes, monocytes, hemoglobin, and ferritin. Ethics approval was obtained from the independent review board (IRP) of the Medical Research Center (MRC) in Qatar with MRC number (MRC-01-21-167| Amendment - 01). Patient data were handled with confidentiality according to MRC guidelines.P-value < 0.2 were then entered into multivariate regression models. The covariates included in the multivariable models were age, serum ferritin, WBC, neutrophils, lymphocytes, monocytes, eosinophils, and hemoglobin.Continuous variables were expressed as mean ( ±  SD) or median (interquartile range), while categorical variables were expressed as counts (percentages). All study subjects were classified into quartiles of blood platelet levels, with baseline characteristics including socio-demographic parameters compared among these quartiles. The comparative means and medians of the various study covariates were estimated. Spearman's correlation coefficients were derived for the various study covariates. Categorical and ordinal logistic regression analyses were used to estimate the risk of clinical outcomes associated with percentiles of serum platelet levels. The estimated odds ratios (ORs) and 95% confidence intervals (CIs) for higher quartiles were compared to the lowest quartile. Unadjusted estimates of the relationship between various study covariates and lower percentile platelet count were derived through bivariate regression analyses. Variables with a Further sensitivity analyses were carried out to ascertain the robustness of our findings. As previous studies have shown the predictive potential of endothelial dysfunction markers in identifying patients with COVID-19 who could potentially require ICU admission, multivariate analyses with and without these markers were performed to ascertain any shift in our point estimate. All analyses were performed using Stata .A summary of the socio-demographic and laboratory characteristics of the study population is shown in p < 0.05) in patients with low platelet counts. For the markers of inflammation and endothelial dysfunction, an increase in the risk of death and/or ICU admission in the setting of thrombocytopenia was associated with increasing serum ferritin . A mild but significant increase in death and/or ICU admission with increasing ALT  and ALP  levels were also observed in patients with low platelet count. In contrast, lymphocyte count  and hemoglobin  were associated with decreased risk of death and/or ICU admission.p = 0.006). Out of the three markers of endothelial dysfunction evaluated, only serum ferritin showed a trend toward predicting ICU admission or mortality in patients with lower platelet count . Pathology of endothelial cell dysfunction in COVID-19 patients’ autopsies showed the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. This could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19.Endothelial dysfunction is a principal determinant of microvascular dysfunction with subsequent organ ischemia, inflammation with associated tissue edema, and a pro-coagulant state.in vitro. In the study by Zhi Lin et al., serum ferritin was an independent risk factor for predicting COVID-19 severity.Ferritin plays an important role in intracellular iron storage. Serum ferritin is also widely recognized as an acute phase reactant and marker of acute and chronic inflammation. It is non-specifically elevated in a wide range of inflammatory conditions. Ferritin secretion is increased by iron and the cytokines interleukin-1-β (IL-1) and tumor necrosis factor-α (TNF-α)  Previous research suggested that high D-dimer levels could predict disease severity, lung complications, and thromboembolic events in COVID-19 even before they occur. A meta-analysis of 12 studies that included 2801 patients found a significant association between high D-dimer and increased severity of COVID-19. There is still controversy regarding the mechanism causing the increase in D-dimer levels. It is possible that this effect results only from an increase in fibrin formed in COVID-19 infection.D-dimer is a fibrin degradation product released into the circulation following fibrinolysis of blood clots. It has two D fragments of the fibrin protein attached by a cross-link.p = 0.001). However, this trend was not observed in patients in the lower percentile of platelet count , which can be explained by a reduction in sample size. We attribute this lack of findings in these markers to a low number of observations for D-dimer and IL-6, as not all participants have undergone testing for these measures. Our study included hospitalized and non-hospitalized patients who were managed according to COVID-19 local guidelines during the first wave of COVID-19 in QatarAmong the three chosen markers of endothelial dysfunction and inflammation, serum ferritin showed a trend toward predicting ICU admission or mortality in our study population  and D-dimer . Our study supported this as we found that increasing age was associated with increased mortality and/or ICU admission among diabetic patients with low platelets.Pre-existing endothelial dysfunction is observed in patients with diabetes, among other conditions. The US Centers for Disease Control and Prevention has reported that diabetes prevalence rises with increasing severity of COVID-19, from 6.4% in non-hospitalized patients to 24.2% and 32.4% in hospitalized and ICU patients, respectively. In another retrospective cohort study of 380 patients, thrombocytopenia was implicated in increasing mortality in patients with COVID-19. Our cross-sectional study was conducted because of the scarcity of literature on the prognosis of COVID-19 specific to patients with diabetes, thrombocytopenia, and elevated markers of endothelial dysfunction. To our knowledge, this study represents the first attempt at exploring the role of various thresholds of platelet counts in augmenting the risk of adverse outcomes in type 2 diabetic patients with COVID-19-related endothelial dysfunction. Consistent with earlier reports in high-risk COVID-19 patients, we found that advancing age consistently predicts the risk of ICU admissions among type 2 diabetic patients with thrombocytopenia. This undoubtedly provides an additional hematological marker for clinical risk stratification in these highly vulnerable patients. We also found that serum ferritin is a potential predictor of ICU admission and mortality in this population.It is evident that thrombocytopenia is associated with adverse outcomes. In a study of 167 confirmed cases of critically ill COVID-19, thrombocytopenia was associated with the deterioration of respiratory function. Low baseline platelet count was also associated with subsequent and long-term mortality.In a cohort of patients with type 2 diabetes and COVID-19 clinical syndrome, thrombocytopenia in the setting of advancing age was associated with a multiplicative risk of both ICU admission and death. Study findings can be used in adjusting available prognostic scoring systems to increase the accuracy and validity of prognosis estimation. Furthermore, it can help guide hospital protocols for risk stratification of patients for admission, which is necessary for triaging COVID-19 patients who may develop severe disease.Our study represents an attempt to stratify the risk of patients with diabetes mellitus who contract COVID-19. Our results demonstrate the increased risk of mortality and ICU admission in patients with low platelet counts and increasing age. Conducting a prospective study that will include diabetic patients and non-diabetic controls and require more standardized inclusion criteria, including relevant laboratory tests, would result in more robust outcomes.The authors confirm that they have no conflict of interest in conducting this study. Approval was obtained from the independent review board (IRP) of the Medical Research Center (MRC).


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with different resistance levels to existing immunity have recently emerged. Antibodies that recognize the SARS-CoV-2 spike (S) protein and exhibit neutralizing activities are considered the best correlate of protection and an understanding of humoral immunity is crucial for controlling the pandemic. We thus analyzed such antibodies in individuals recovered from infection in 2020 as well as vaccinees after two doses of an mRNA vaccine.Neutralizing antibody responses against three SARS-CoV-2 variants  were determined in serum samples from 54 infected individuals  and 34 vaccinees shortly after symptom onset or second vaccination, respectively, as well as six months later. In addition, the effect of the S sequence of the infecting strain on neutralization was studied.Non-hospitalized patients had the lowest neutralization titers against all variants, while those of hospitalized patients equaled or exceeded those of vaccinees. Neutralizing activity was lower against the two VOCs and declined significantly in all cohorts after six months. This decrease was more pronounced in hospitalized and vaccinated individuals than in non-hospitalized patients. Of note, the specific neutralizing activity  was higher in the infected cohorts than in vaccinees and did not differ between non-hospitalized and hospitalized patients. Patients infected with viral strains carrying mutations in the N-terminal domain of the spike protein were impaired in Beta VOC neutralization.Specific neutralizing activities were higher in infected than in vaccinated individuals, and no difference in the quality of these antibodies was observed between hospitalized and non-hospitalized patients, despite significantly lower titers in the latter group. Additionally, antibody responses of infected individuals showed greater heterogeneity than those of vaccinees, which was associated with mutations in the spike protein of the infecting strain. Overall, our findings yielded novel insights into SARS-CoV-2-specific neutralizing antibodies, evolving differently after virus infection and COVID-19 vaccination, which is an important issue to consider in ongoing vaccine strategy improvements. Since its emergence, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into multiple variants, some with mutations that affect their biology, spread and transmissibility. These include the variants of concern (VOCs) Alpha, Beta, Gamma, Delta and the most recently emerged Omicron, which exhibit different levels of immune escapeNeutralizing antibodies are predictive for protection against disease  , but theThe majority of the neutralizing activity after infection is attributable to antibodies binding to the receptor-binding domain (RBD) of the surface spike glycoprotein (S) –11. The As neutralizing antibodies play a critical role in preventing virus infections, we investigated the humoral immunity in hospitalized and non-hospitalized patients as well as mRNA vaccinees early after disease onset or the two-dose vaccination, respectively, and six months later, including neutralization of three SARS-CoV-2 variants . We found that the specific neutralizing activity  is higher in infected than in vaccinated people regardless of severity of disease and the sampling time point. In addition, the range of these ratios was larger after infection than after vaccination. Analysis of spike sequences in patient swabs indicated that the observed heterogeneity was associated with additional mutations in the NTD of the infecting virus strain.All patients  had been diagnosed with SARS-CoV-2 infection by PCR testing from nasal swabs or respiratory secretions between March and November 2020, excluding the possibility of infection with a VOC. All patients gave written informed consent before being included in the study.Serum samples after the second dose of the BNT162b2 mRNA vaccine from healthcare workers were sent to the diagnostic laboratory of the Center for Virology for antibody titer determinations, and anonymized leftover samples were used for our analyses. SARS-CoV-2 infections were ruled out by regular PCR testing of the vaccinees.Serum samples were collected approximately three weeks after infection/vaccination  as well as approximately six months later . Median time to sample collection after symptom onset or second vaccination was similar in all cohorts, as shown in The analyses were approved by the local ethics committee of the Medical University of Vienna (EK-No. 1291/2021 and EK-No. 1926/2020).The D614G, Beta and Delta SARS-CoV-2 strains were isolated from nasopharyngeal swabs from COVID-19 patients. Vero E6 cells ECACC 85020206) were infected and incubated at 37°C until a cytopathic effect occurred. Cell culture supernatant was harvested and the presence of SARS-CoV-2 was confirmed by PCR. The virus isolates were then passaged two more times in Vero E6 cells. All isolates were controlled to be free of other respiratory viruses by PCR as described . The cleaned, indexed libraries were pooled in equimolar ratios and sequenced on an Illumina MiSeq, using V2 chemistry in paired reads of 150 bp in each direction. Sequencing reads were demultiplexed, quality trimmed, and aligned to the Wuhan-Hu-1 reference sequence (GenBank accession number: NC_045512.2) by the BWA-MEM software package . Primer Spike-specific IgG antibodies were quantified in binding antibody units (BAU)/ml using the WANTAI SARS-CoV-2 IgG ELISA kit . The test is based on the RBD of the original strain isolated in Wuhan and was performed according to the manufacturer’s instructions. Samples were serially diluted until the endpoint in all instances.50 SARS-CoV-2  for one hour at 37°C before the mixture was added to Vero E6 cell monolayers (starting dilution of samples 1:10). After three days, NT titers were expressed as the reciprocal of the serum dilution required for protection against virus-induced cytopathic effect. NT titers ≥10 were considered positive.The live virus neutralization tests (NT) were performed as previously described . BrieflyStatistical analysis was performed with GraphPad Prism (Version 9.2.0). For longitudinal analyses, only samples from patients available at both the early and late time points were included. Seven additional early samples were included in the spike sequence analyses Figure 6post hoc test) or Mann-Whitney test (2 groups). In the case of NT titers < 10, a value of 5 was used for these analyses. Fold reductions of antibody levels over time were calculated for each patient individually using the following formulas:RBD-ELISA BAU/ml and NT titers were compared with the Kruskal-Wallis test or a paired t-test (two groups). The ranges of NT/ELISA ratios were expressed as maximum-to-minimum factors, which were calculated by dividing the maximum ratio through the minimum ratio for each cohort, time point and virus variant, respectively. Spearman’s rho was applied to evaluate the correlation between the test results (ELISA and NT), to assess the correlation between NT titers against different variants, and the correlation between ELISA, NT or NT/ELISA ratios and the time point of sample collection (days post onset/2nd vaccination), respectively. The coefficient of determination (R2) was used to assess variability.Specific neutralization (NT/ELISA ratios) was calculated for samples that were positive in both assays and log-transformed for ANOVA  and 34 individuals after a two-dose mRNA vaccination (BNT162b2).SARS-CoV-2 infection was diagnosed by RT-PCR from nasal swabs or respiratory secretions. Non-hospitalized patients showed a mild to moderate course of the disease. Thirteen of 30 (43%) hospitalized patients were treated in intensive care units Table 1.Serum samples were taken at two time points. The first sample was collected approximately three weeks post symptom onset or the second vaccine dose . Follow-up samples were collected approximately six months later . As shown in P < 0.0001), whereas hospitalized and vaccinated individuals developed similar amounts of antibodies  and the two VOCs Beta (B.1.351) and Delta (B.1.617.2). In line with our ELISA results, non-hospitalized patients showed significantly lower NT titers against all virus strains than hospitalized and vaccinated individuals at both time points, whereas hospitalized individuals developed the highest titers against all variants at each time point  Figure 5We found no differences in the D614G NT/ELISA ratios between non-hospitalized and hospitalized individuals at both time points Figure 5To analyze the antibody responses in relation to the time points of sample collection, we performed correlation analyses combining the WT-specific antibody levels as well as the NT/ELISA ratios from all cohorts , ten samples had the D614G mutation only, and samples of eleven patients carried one or two additional substitutions in different regions of S 3 as comIn this study, we provide a comprehensive analysis of the variability of antibody responses in longitudinal cohorts after early-pandemic infection with SARS-CoV-2 and vaccination with an mRNA COVID-19 vaccine. The data presented demonstrate not only substantial differences in the magnitude as well as the functional activity of the induced antibodies, but also a greater heterogeneity of responses in infected than in vaccinated individuals.Non-hospitalized and hospitalized patients developed antibodies with similar functional activities  and most NT titers against the D614G virus were still positive at this time point 3. Only We found that the range of specific neutralizing activities after SARS-CoV-2 infection was larger than after COVID-19 vaccination , 16. OneOur results also have practical implications. Neutralizing antibodies are important for assessing the quality of immune responses, but NTs are more time-consuming than ELISAs and require the handling of infectious virus. It would thus be of interest to relate ELISA values to NT titers and define a BAU/ml threshold for neutralization, which, however, has to take the source of immunity into account. Even more complex is the relation of these values to protection, as Fc-mediated effector functions of non-neutralizing antibodies can also play a role , 38. TheThe datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/The studies involving human participants were reviewed and approved by the Local ethics committee of the Medical University of Vienna (EK-No. 1291/2021 and 1926/2020). The patients provided their written informed consent to participate in this study.KS, JA and MG: conceptualization and writing. KS, JC, SA: methodology. KS, JA, MG, JC, SA: investigation. JA, MG, E-PS, LW, MT, WH, AZ: resources. JA: funding acquisition. KS and JA: supervision. All authors contributed to the article and approved the submitted version.The study was supported by the Medical-scientific fund of the Mayor of the federal capital Vienna [grant Covid003].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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Therefore, using a DL-based algorithm on true-colour confocal scanning and UWF fundus imaging, we confirmed that both confocal fundus imaging techniques had high value in diagnosing glaucoma.In this retrospective, comparative study, we evaluated and compared the performance of two confocal imaging modalities in detecting glaucoma based on a deep learning (DL) classifier: ultra-wide-field (UWF) fundus imaging and true-colour confocal scanning. A total of 777 eyes, including 273 normal control eyes and 504 glaucomatous eyes, were tested. A convolutional neural network was used for each true-colour confocal scan  and UWF fundus image  to detect glaucoma. The diagnostic model was trained using 545 training and 232 test images. The presence of glaucoma was determined, and the accuracy and area under the receiver operating characteristic curve (AUC) metrics were assessed for diagnostic power comparison. DL-based UWF fundus imaging achieved an AUC of 0.904 : 0.861–0.937) and accuracy of 83.62%. In contrast, DL-based true-colour confocal scanning achieved an AUC of 0.868 (95% CI: 0.824–0.912) and accuracy of 81.46%. Both DL-based confocal imaging modalities showed no significant differences in their ability to diagnose glaucoma ( Glaucoma is a chronic, progressive optic nerve disease with characteristic visual field (VF) impairment resulting from the loss of the retinal nerve fibre layer (RNFL). The early diagnosis of the disease is difficult because the symptoms are not clear until it has progressed to the end stage. Nevertheless, early diagnosis is important for preventing visual impairment caused by glaucomatous damage. The visualisation of RNFL defects is a useful indicator for the early detection of glaucomatous damage ,2,3,4,5.Several imaging devices are used to diagnose glaucoma. As many types of imaging methods can be used, physicians usually integrate the results obtained from multiple methods and perform the diagnosis based on such. Therefore, efforts to improve diagnosis using various imaging methods have been made in the fields of ophthalmology and glaucoma .Recently, high-resolution fundus imaging via confocal scanning has been developed and has begun to be widely used in clinical practice. Ultra-wide-field (UWF) fundus imaging and true-colour confocal scanning are widely performed. High-resolution fundus imaging equipment uses a confocal scanning laser method. UWF fundus imaging  combines data captured using red and green laser sources. It is advantageous in that it is possible to capture the data within a short time period without mydriasis and observe a wide range of peripheral retinas ,10. TrueMany efforts have been made to incorporate deep learning (DL) into various imaging methods for diagnosing ophthalmologic diseases ,23,24,25Some studies have shown that UWF fundus imaging is useful for diagnosing glaucoma , whereasIn a previous study conducted by our team, true-colour confocal scanning was found to be superior to UWF fundus imaging in detecting localised RNFL defects (early changes in glaucoma) when eye physicians manually evaluated images taken using both modalities ,30,31. IThe study protocol was approved by the institutional review board of Hanyang University Hospital. This study design followed the tenets of the Declaration of Helsinki for biomedical research.In this retrospective, cross-sectional study, we investigated 777 eyes, which included 273 healthy eyes and 504 glaucomatous eyes. All participants visited the glaucoma clinic of Hanyang University Hospital between August 2019 and August 2021. All of them underwent an ophthalmologic examination, including a visual acuity test, slit-lamp examination, intraocular pressure (IOP) measurement using Goldmann applanation tonometry, gonioscopy, axial length measurement , stereo disc imaging, red-free RNFL imaging (Eidon AF™), Swedish interactive thresholding algorithm 24-2 perimetry , and swept-source OCT .The definition of a normal VF, glaucomatous VF defects, and the reliability of the VF test was determined according to the classical method used in many previous studies in the literature .Patients with best-corrected visual acuity ≥ 20/40, refractive errors within a ±6.0 D spherical equivalent, and a ±3.0 D astigmatism were included in this study. Exclusion criteria were a history of surgical therapy , any other ocular disease that could affect visual function, any media opacity that would significantly hinder OCT image acquisition, and an inability to acquire high-quality images . When both eyes met all the eligibility criteria, one eye was randomly selected for inclusion .Patients with glaucoma were identified on the basis of several clinical signs. Specifically, the presence of a characteristic optic disc  on stereo disc images was used as a major clinical sign for glaucoma diagnosis. The presence of RNFL defects on red-free fundus imaging is an alternative sign, regardless of the presence or absence of glaucomatous VF defects .Healthy patients were defined as satisfying all of the following criteria: (1) patients with no history of intraocular surgery, (2) IOP of ≤21 mmHg with no history of increased IOP, (3) no glaucomatous disc appearance, and (4) normal ophthalmologic findings. Two glaucoma specialists (M.S. and W.J.L.), who were masked to all other patient information, independently judged the images. In order to avoid ambiguity, cases in which the two examiners concluded differently were excluded from the training and test datasets .Convolutional neural networks (CNNs) are widely used in image-recognition tasks. They effectively extract spatial features by conducting two-dimensional convolution with kernels whose weights are determined by training the model with the dataset. Herein, a CNN was applied to detect glaucoma using true-colour confocal scanning and UWF fundus images separately. Among the various CNN architectures, the VGG-19 network was selected owing to its popularity and computational efficiency. The VGG-19 architecture is illustrated in The VGG-19 network consisted of 16 convolution layers and 5 pooling layers. The last layer consisted of the fully connected layer, followed by the softmax function that produced the probability values for each category. It was pretrained with ImageNet. Using the collected dataset, we trained the VGG-19 network to perform a glaucoma diagnosis task. A batch size of 4, a learning rate of 0.001, and an epoch of 40 were used on the basis of empirical parameter tuning.To evaluate the diagnostic ability for glaucoma, we calculated the area under the receiver operating characteristic curve (AUC) and accuracy. The cut-off value for glaucoma probability was changed using the AUC of the 95% CI, and the accuracy was used as a measure of precision when classifying the stages of glaucoma. The precision–recall curve is a metric for evaluating the model of the classifier and is used when the distribution of data labels is uneven. The x-axis represents the recall, and the y-axis represents the precision. The area value is used to evaluate the performance of the binary classifier.p-values of <0.05 were considered significant. Values were expressed as means ± standard deviations. Statistical tests were performed using SPSS v24 , MedCalc , and the PyTorch framework using Python  [CA, USA) .We split the entire dataset into training and test datasets at a ratio of 7:3. The demographic and clinical characteristics of the participants are summarised in As shown in In addition, as shown in the AUC and precision–recall curve in p-value between the two confocal imaging modalities was 0.135, thereby indicating no significant difference. The analysis shows that the AUC of the DL-based imaging methods did not significantly differ from that of the traditional OCT parameter-based methods .In this study, we investigated the performance of DL-based UWF fundus imaging and true-colour confocal scanning in diagnosing glaucoma. We applied DL algorithms to these two relatively recent confocal fundus imaging modalities and found that they exhibited good glaucoma diagnostic abilities compared to those of conventional OCT parameter-based methods.Although DL has been used for diagnosing glaucoma in several studies ,29,30,31Because of the high resolution of the images, true-colour confocal scanning has been used to evaluate some retinal diseases. Some studies used true-colour confocal scanning using the EyeArt software to diagnose diabetic retinopathy ,37. ThesHerein, we used VGGNet among the various available architectures for imaging analysis  ,41,42. VWe compared the diagnostic ability of the methods based on DL with that of conventional methods based on the peripapillary RNFL, macular GCIPL, and macular GCC thickness values. The conventional methods employ widely used OCT parameters for diagnosing glaucoma. Our analyses showed that the diagnostic ability of the DL-based methods was not significantly different from that of existing OCT parameter-based methods. Our study suggests that the accuracy of glaucoma diagnosis is comparable between OCT parameter- and DL-based methods.Many studies have applied DL to fundus images ,32,34,35Our team compared UWF fundus imaging and true-colour confocal scanning for detecting localised RNFL defects in a previous study , in whicUnlike the comparison made by glaucoma specialists , our anaThe technical differences between UWF fundus imaging and true-colour confocal scanning are as follows: (1) differences in light source: a two-wavelength laser light versus an LED and a difference between false colour and true colour; (2) the confocal aperture of UWF fundus imaging is circular, whereas true-colour confocal scanning uses a confocal slit; and (3) there is a difference in the distortion owing to the different capture ranges of the two devices used.These factors can cause differences in the interpretation of images by physicians (humans). These are possible disadvantages of UWF fundus imaging when DL is used to detect glaucoma instead of physician observations. Interestingly, the relatively distorted UWF fundus image showed a comparable diagnostic performance to the true-colour confocal scanning image (after adopting AI). Imaging not only the optic nerve but also RNFL defects is very important in diagnosing glaucoma, although the primary origin of glaucomatous damage is the optic nerve.This study has several limitations. First, a direct comparison between the DL algorithm and judgement by physicians was not performed. Instead, we compared DL with OCT parameters that are often used. Second, because conventional fundus images or red-free images were not available, a direct comparison was difficult. When physicians discriminate against glaucoma and set the gold standard for comparison, it would be a major disadvantage to use a true-colour confocal scanning image instead of a red-free image. However, true-colour confocal scanning images have been used for the diagnosis of glaucoma in many previous studies instead of red-free images ,43,44, aOur study results confirmed that the ability of DL-based UWF fundus imaging and true-colour confocal scanning to diagnose glaucoma was comparable to that of OCT parameter-based methods. By adopting DL, these two recently developed confocal fundus imaging systems are expected to be useful for glaucoma diagnosis.