Absolute quantitative myocardial perfusion SPECT requires addressing of aleatory and epistemic uncertainties in conjunction with providing image quality sufficient for lesion detection and characterization. Iterative reconstruction methods enable the mitigation of the root causes of image degradation. This study aimed to determine the feasibility of a new SPECT/CT method with integrated corrections attempting to enable absolute quantitative cardiac imaging .TM) acquired at rest from 56 patients aged 71 ± 12 y with suspected coronary heart disease. The xSC prototype comprised list-mode acquisitions with continuous rotation and subsequent iterative reconstructions with retrospective electrocardiography (ECG) gating. Besides accurate image formation modeling, patient-specific CT-based attenuation and energy window-based scatter correction, additionally we applied mitigation for patient and organ motion between views (inter-view), and within views (intra-view) for both the gated and ungated reconstruction. We then assessed image quality, semiquantitative regional values, and left ventricular function in the images.We compared images of prototype xSC and conventional SPECT  were observed on xSC images. Wall motion, 16-gate volume curve, and ejection fraction were at least acceptable, with indication of improvements. The clinical prospectively gated method rejected beats ≥20% in 6 patients, whereas retrospective gating used an average of 98% beats, excluding 2% of beats. We used the list-mode data to create a product equivalent prospectively gated dataset. The dataset showed that the xSC method generated 18% higher count data and images with less noise, with comparable functional variables of volume and LVEF (p = ns).Quantitative myocardial perfusion imaging with the list-mode-based prototype xSPECT Cardiac is feasible, resulting in images of at least acceptable image quality.The online version contains supplementary material available at 10.1007/s12350-023-03374-5. Since then, several limitations of SPECT imaging have been revealed in terms of quantitation and repeatability. Currently, the most prevalent means of evaluating SPECT images remain with visual interpretation, semiquantitative scoring, and left ventricular function assessment.6 Furthermore, both attenuation (AC) and scatter (SC) corrections are routinely used in 31% of institutions with an iterative reconstruction method. SPECT reconstructions done by FBP are not corrected for attenuation and scatter. Nuclear cardiologists require training to adequately interpret myocardial perfusion images, while considering the possibility of image artifacts. In the process of iterative image reconstruction, we need to consider the impact of inadequate compensation of patient-induced tomographic inconsistencies. A tomographic inconsistency occurs when the data model does not reflect the reality of the actual acquisition and can be caused by, e.g., patient attenuation, scatter, beating hearts including arrhythmia, respiratory, and body movements. Tomographic inconsistencies might develop image artifacts, becoming typically more noticeable as iteration updates increase. Although some of the image degrading factors have been investigated individually, to our knowledge, there has not been an evaluation of the impact on image quality in myocardial SPECT when all these corrections are used simultaneously. This is of importance, as the statistical quality of data can only justify a limited number and degree of corrections. Each correction method requires estimable parameters, hence, the primary concern that corrections follow the “do-no-harm” paradigm, i.e., guarding against insufficient data with too many parameters that might yield to instability, revealing as artifacts and poor reproducibility and repeatability.Image reconstruction with filtered back projection (FBP) is used in 49% of Japanese institutions, ordered-subset expectation maximization (OSEM) in 30% , and both FBP and OSEM in 21%.The present study aimed to determine the feasibility of integrated and automated corrections attempting to enable absolute quantitative cardiac imaging, improve reproducibility and repeatability, and to find ways to further improve SPECT image quality by mitigating patient attenuation, scattering, overall tomographic inconsistency due to patient body motion and respiratory motion. We used retrospective gating to more effectively account for cardiac contraction with/without arrhythmia, and allowed for continuous rotation, thus, maximizing the data collection.2) who were included for comparisons of perfusion at rest. The summed rest score (SRS) determined automatically using standard databases by the Japanese Society of Nuclear Medicine normal database was 6.9 ± 6.6 (range 0-24).7This study included 56 patients  with definite or suspected CAD who were assessed by myocardial perfusion imaging (MPI) (Table 99mTc-methoxy-isobutyl-isonitirile (MIBI) (n = 49) or tetrofosmin (n = 7), and at rest with 700 MBq (18 mCi) of the same tracers.The resting part of stress-rest MPI was used from a one-day protocol study. All patients fasted during the morning and refrained from taking any medications that might affect the MPI results. The patients were then assessed under stress by adenosine SPECT imaging using 260 MBq (7 mCi) of 99mTc and a 15% lower abutting scatter window . Sixty projection views over 360° with 6° step-and-shoot sampling were accumulated using a 64 × 64-matrix with a zoom factor of 1.45 (6.6-mm pixels), 35 seconds per view in a tight circular orbit (rotation radius of 24 cm).Conventional SPECT images were acquired at Kanazawa University Hospital using a Symbia Intevo 16 SPECT/CT and our routine clinical protocol comprising of AutoForm™ low-energy high resolution collimators with a 15% peak window, centered at 140.5 keV for 57Co-source was used to calibrate the SPECT imager per xSPECT Quant TM protocol. The prototype A 3%-NIST traceable calibrated TM for conventional ungated and gated reconstructions, with a distance-dependent, 3D-Gaussian collimator model for the point spread function within OSEM at 120 updates (12 subsets and 10 iterations) based on corrected framed data. A 3D-Gaussian filter at a full-width at half maximum (FWHM) of 13.2 mm was used for post smoothing. We do not typically use CT attenuation correction in clinical practice at our hospital.We used our clinical standard Flash3DTM from list-mode data using a measured 3D point response function, 3D rotation with adaptive class-standard gantry deflection, CT-derived attenuation correction (AC), and energy window-based scatter correction (SC) as described by Vija et al..10 In this work, we chose the OSEM-based xSPECT Quant reconstruction, as it yields a more similar resolution and noise impression to the Flash3D reconstruction.The xSC reconstruction was based on xSPECT Quantinter-viewintra-viewThe xSC reconstruction contained retrospective gating, Retrospective gating: Retrospective gating enabled efficiency improvement by allowing continuous rotation in gated studies thereby maximizing the counts utilized for each view. In the xSC reconstruction, a beat histogram was curated using automated data analysis for outliers,11 where the acceptance window was defined with ± 3 root-mean square of the median in an iterative process run to convergence (“curation”). The curation rejected so defined premature ventricular contraction and 1 beat after it. This process was an attempt to maintain the maximum number of counts possible even when abnormal cardiac rhythms presented a challenge to the prospective approach. In addition, it reduces tomographically inconsistent assignments of gate to angle that may occur in the prospective scheme resulting in, e.g., radial blurring and then potentially impacting LVEF assessment.12 Albeit any number gates are in principle possible, we also selected 16 gated frames as a good trade-off between volume curve sampling and statistical power. Each xSC gate was reconstructed with attenuation and scatter correction.We checked for beat histogram consistency in the back-to-back clinical and dedicated-research acquisitions, to exclude a temporal bias due to sequenced acquisition. We applied the same prospective gating and framing algorithm to the list-mode data as implemented in the clinical product which framed them with a 20% acceptance window and auto-tracking. We examined six patients with frequent arrhythmia and outlier beat lengths, and 12 without arrhythmia during data acquisition.Inter-view motion “correction”: Its goal was to reduce tomographic inconsistencies, mitigating a build-up of image artifacts as updates progress. It was designed to be automated and compatible with iterative reconstruction. However, it is limited by poor count statistics and the fundamental limitations of the image formation. The key difference between conventional and this new approach is briefly described in the following (see details in supplement file Section A). The current commercially available proprietary semi-automatic method was based on estimation of axial and transaxial motion in each projection view to mitigate cardiac motion induced by patient motion or cardiac creep. Transaxial and vertical motion estimations were based on sinograms and linograms, respectively, and the projections were shifted view-by-view in axial and transaxial direction prior to reconstruction.14 Fundamentally, the method suffered when significant change of contrast of the myocardial projection occurred due to patient-specific factors. The contrast can fall so low that edge detection and subsequent fits become unreliable in some views, and potentially inducing erroneous shifts in these views. Manual intervention is often needed, which is subjective and rarely repeatable, resulting in a trial-and-error reconstruction approach. The inter-view motion correction overcomes this issue using a fully automated method applicable to all study types including cardiac studies, which allows for rigid axial and transaxial shifts measured within and was designed for the iterative reconstruction process.15 The shift vectors were estimated in a dedicated automated reconstruction preceding the user-adjustable target reconstruction. This dedicated reconstruction named “Improving Tomographic Consistency” (ITC)-reconstruction used the same update method, data model, and enables AC and SC as the target xSC reconstruction. It was not user adjustable and solely for the purpose of shift vector estimation. The xSC reconstruction restarted using the shift vectors from the preceding ITC reconstruction by updating the 3D rotation matrix, thereby improving tomographic data model consistency for all views. Strictly speaking this approach represents a motion correction only if the tomographic inconsistency was caused by a rigid-body axial and transaxial motion, otherwise it is merely a mitigation.Intra-view motion “correction”: This refers to mitigating for motion effects during the acquisition of a view for the duration of the dwell time at the specific viewing angle . The method can mitigate the impact of motion during the dwell time for both continuous and discontinuous rotation if the statistical data quality allows it. Respiration is typically the main cause for such motion. However, respiratory-induced cardiac motion may also show up as view-to-view jitter, a type of inconsistency appearing over neighboring views. This type of residual inter-view jitter is more noticeable when the dwell time is on the order of the respiration period, which can be addressed by the subsequent use of inter-view motion correction. We used the non-linear Laplacian Eigenmap data-driven dimensionality reduction approach based on the assumption that the respiration information data laid on a lower-dimensional manifold.18 The data-driven gating subdivided the projection view into respiratory-gated views (RGV). In essence, the dwell time was split into six estimated respiratory gates of unequal temporal duration to create six RGV’s, enabling an estimate of the center-of-light inter and intra-view motion correction method by applying patient-derived shift vectors to a perfectly still phantom dataset, thereby inducing the artifacts expected of the respective type of inconsistency. We used data from an anthropomorphic normal male cardiac phantom  acquired in the same configuration as the xSC. The shift vectors were extracted from patients, and histograms of all the transverse (x) and axial (y) shift vectors of the patient data were generated.We assessed the potential improvement on image quality of the Two experienced nuclear medicine physicians and a technologist visually assessed vertical and horizontal long- and short-axis images reconstructed by conventional and xSC methods. They compared the quality of blinded images, noise, artifacts, the possibility of false defects and a previous myocardial infarction if it had been clinically diagnosed prior to this study.All beat lengths during SPECT data acquisition were analyzed using RR interval histograms, and fractions of beats within the 20%-acceptance window beat length were measured. Images were reconstructed and displayed as long- and short-axis images using 4DM software  with standard 17-segment polar map display and segmental count (%) calculations. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) were compared between prospective and retrospective gating methods. Echocardiographic measurements of volume and EF (modified Simpson method with four- and two-chamber views) within 3 months of an MPI study served as the reference. Cross-sectional and circumferential profiles were analyzed at the mid-portion of transaxial SPECT images as well as slices with perfusion defects to evaluate contrast.The Ethics Committee of Kanazawa University approved this collaborative study. All included patients provided written informed consent to participate.All data are expressed as means ± standard deviation (SD), and means were compared using the analysis of variance. Categorical variables were analyzed using contingency tables. Segmental counts on polar maps were assessed using paired-comparison tests. Linear regression was calculated using the least-squares method. All data were statistically analyzed using JMP Pro v. 16.0 . Values with P < 0.05 were considered significant.Diagnoses were classified according to findings of perfusion defects and function as large infarction , small to intermediate infarction , heart failure without perfusion defects , and near-normal perfusion and function .The visual quality of xSC images was judged as better (44%) and comparable (56%) to those of conventional SPECT images. False defects were not evident in 75% of patients’ images when reconstructed by both methods. However, the conventional method gave a false impression of hypoperfusion in the inferior wall in 23% of the patients. Myocardial infarction was diagnosed by both methods in 20 91%) of 22 patients. Seven percent of images reconstructed with xSC were considered noisy. In general, xSC images showed thinner myocardial walls, more homogeneous distribution in walls, and higher image contrast than conventional Flash3D images  were measured using a polar map Figure . In thisDifferences in image characteristics can also be determined by profile analysis. Figure intra and inter-view motion correction approach is shown in Figures inter-view motion to x- and y-directions in this case apparently resulted in an artifactual heterogeneity in the polar map distribution , ESV , and LVEF  . In the group with near-normal perfusion and function , mean EDVs, ESVs and LVEFs, for males and females were 91  and 91 (55-118) mL; 33 (18-62) mL and 27 (15-44), mL and 65% (56%-74%) and 70% (62%-74%), respectively, using the xSC method.Correlations between xSC and conventional methods were computed for EDV (R) Figure . The EDV19The prospective image generation using list-mode and clinical prospective acquisitions allowed comparisons of two gating strategies with separately acquired data. We also confirmed that the beat histogram characteristics remained unchanged in a back-to-back study as described.The following results were generated from a comparison of retrospective and prospective gating methods, in which all corrections were applied. When all heart-beat lengths were analyzed, conventional prospective gating and xSPECT with a 20% window accepted 89% ± 20% and 98% ± 2% of beats, respectively Figure A. A sign22 Patient motion correction during data acquisition, if present, also contributes to accurate quantitation.23 Electrocardiogram gating to exclude arrhythmic heartbeats is essential when imaging a beating heart and further correction of respiratory motion might improve image quality and patient-by-patient variability.26 However, the combined effects of such corrections have yet to be determined and they are not necessarily applied in clinical practice. We found that the integrated corrections for the SPECT images using a list-mode data acquisition are technologically and clinically feasible and significantly improved image quality by visual assessment without any noticeable pitfalls. We also assessed LV function by retrospective gating while fully maintaining the acquisition counts during data acquisition.The ideal characteristics of SPECT images include accurate measurements of tracer accumulation and quantitative images that are sufficient for evaluating regional myocardial uptake and estimating functional parameters. Attenuation and scatter correction incorporated into an ordered subset/maximum-likelihood expectation maximization (OSEM/MLEM) method has been recommended to achieve optimal SPECT image reconstruction.27 Attenuation correction has been established since the mid 1990s as a strategy to improve the diagnostic accuracy of the inferior wall.20 The American Society of Nuclear Cardiology (ASNC) and the Society of Nuclear Medicine also affirmed that AC should be regarded as an evolving standard for SPECT.28 However, users found the method cumbersome in clinical practice, as well as hardware and manufacturer dependent.29 With advances in SPECT-CT technology, the ASNC has recommended the standard application of AC21 in nuclear medicine facilities. To avoid misinterpretation by AC artifact, a combination of conventional non-AC image and adjunct AC images are generally recommended. Scatter correction is also required to compensate for over-correction in attenuated deep regions. However, only 30% of Japanese institutions use both AC and SC. In the present study, activity in inferior walls was mistakenly identified as reduced in as many as 23% of non-AC cases, while application of AC and SC allowed correct identification of these cases as normal. Figure Attenuation and scatter corrections are considered indispensable to ensure quantitative accuracy. We found that the myocardial wall count distribution became homogeneous in the polar map analysis Figure . Althouginter-view motion correction. We showed the potential of the methods to improve count distribution pattern and edge. However, the impact of the inter-view motion correction in clinical images was not apparent. For one the histogram only showed very small shifts of only a few mm, indicating essentially no relevant motion as assessed by the rigid-body translational model. Nonetheless, the method was safely applied during reconstruction without generating harmful artifacts and contributed to steadying the procedure.Another improvement applied herein was the mitigation of tomographic inconsistencies incurred during projection image acquisition such as from motion. We quantified inconsistencies by determining shift vectors in the iterative reconstruction process including AC and SC, as a proxy for motion. The xSC method used a fully automated method during reconstruction that allowed rigid axial and transaxial shifts to improve tomographic consistency as assessed by the reconstruction method. Fully 4D motion correction was not possible given the multi-channel collimator image formation resulting in noisy data. Practical approximations must therefore be made to avoid having too many variables for too little data, and thus we corrected only in axial and transaxial direction and for each view separately. Therefore, it was not an anatomically correct motion correction, but a mitigation, as only tomographic consistency within the rigid translational model can be improved, regardless of the actual root cause of the inconsistency. We demonstrated the effect of organ motion on image quality, by applying patient-derived shift vectors on a resting phantom to visualize the effect Figures , emulati25 Anzai pressure belt  was able to track displacement of the abdominal wall, and applied to dynamic positron-emission tomography imaging.30 In contrast, data-driven methods for extracting respiratory surrogate signals from SPECT list-mode data have been proposed, and a validation study of 67 patients found a mean correlation against the Anzai belt of 0.81 ± 0.17.16 We used the data-driven approach to the present study as it is convenient for clinical practice. In general, respiratory motion patterns vary among patients and cannot be estimated in advance as indicated by the boxplot of each respiratory gate , which could happen in clinical studies, the effects were apparently visible on the still phantom image  and the auto-tracked RR interval. Moreover, correlations of functional parameters of EDV, ESV, and LVEF were acceptable even when prospective gating data with a 20% window were simulated using the acquired list-mode data. Data acquisition with variable beat length in patients with arrhythmia resulted in reduced total counts especially during the last part of RR intervals, which subsequently increased noise in the reconstructed images. Retrospective gating from list-mode used 98% of the data and contributed to stable image reconstruction. Since list-mode data included all information about detected gamma-ray position, energy, and timing of events, the most important advantage is the generation of images of almost equal statistical quality under arbitrary beat histogram conditions. Although such quantitative merits are established and applied to clinical gated blood-pool investigations and animal studies,35 A comparison of averages between narrow-and non-windowed LVEF revealed a good correlation between the two approaches. Therefore, the LVEF averaged by including most of the beats might be used as a standard even for gated SPECT if LVEF is the purpose of the study. However, contamination with arrhythmic beats could interfere measurement accuracy if the purpose of the study is to determine functional diastolic filling.32 A study of the influence of various arrhythmia types on gated SPECT images revealed minimal changes in LVEF (1% ± 4%) and volumes (2% ± 9%) compared to controls, whereas end-frame count loss rendered wall thickening calculations and perfusion analyses inaccurate.37The acceptable fraction of beats must be considered when imaging patients with serious arrhythmia and large variations in RR intervals. Frequent premature contractions and subsequent beats in patients have commonly been excluded. In contrast, LVEF differs in patients with atrial fibrillation with and without windowing, and how it varies with cycle has been determined in a study that included a gated blood pool.38 It is reported that when combined with correction for motion, depth-dependent blurring, and attenuation correction significantly improved diagnostic accuracy compared to the motion correction alone.22 Notably, integrating all corrections did not generate any harmful artifacts in this study. Lastly, although improving quantitative values by integrating all possible correction methods is desirable, whether pursuing true quantitation would definitively improve clinical diagnostic ability requires further investigation.26The question arises as to whether integrating all corrections is feasible, effective, and practical. Although acquisition and reconstruction conditions between the conventional and xSC methods differed significantly, our aim of this study was not just to compare clinical conditions and highly integrated research condition but also to apply the new corrections to clinical practice. Myocardial SPECT images include fundamental flaws essentially derived from reconstruction by multiple projection images, attenuation, scatter, patient motion, cardiac motion, respiratory movement, and the possible inclusion of arrhythmia. Moreover, the effects of these confounding factors depend on patients and their conditions during data acquisition. For example, AC, motion, and arrhythmia correction could be applied to patients with obesity, unexpected motion, and frequent aberrant beats, respectively. However, we reduced patient-to-patient variability by correcting all known factors that might cause artifacts. Important aspects are new possible artifacts created by advanced correction methods as those associated with AC during the early 2000s.One limitation of this study was that we applied corrections only to rest studies. Since this study aimed to determine the technical feasibility of integrated corrections, we examined imaging characteristics and functional aspects of patients with myocardial infarction.The ground truth for a clinical diagnosis of myocardial infarction relied on patient history, ECG, echocardiography, and coronary angiography findings. Information about coronary flow or fractional flow reserve was not included. The next steps will be to validate the effectiveness and diagnostic utility of the method in stress-rest studies. Our conventional method did not include CT AC. Images with AC are still not popular in Japan, which is partly due to a mean BMI of 23 (only two of our patients had a BMI > 30) and an acquisition arc of 360°. Under such conditions, a beneficial effect of AC has not been recognized in clinical practice. Moreover, the contributions of corrected attenuation, scatter, motion, tomographic inconsistency, and gating methods were not separately and independently evaluated, because an integrated corrections were applied to avoid numerous permutations.inter-view correction of tomographic inconsistency, intra-view motion correction from data-driven respiratory gating, and list-mode-based retrospective ECG gating improved resolution and could deliver repeatable quantitative results. The diagnostic accuracy of perfusion defects using xSPECT Cardiac is at least equal to using conventional SPECT imaging.SPECT images with attenuation and scattering correction, Myocardial SPECT images yield better image quality when attenuation, scattering, respiratory movement, tomographic inconsistency, arrhythmia, and list-mode-based retrospective gating were corrected. Integrated corrections are technologically feasible, creating no harm, and could be effective for clinical studies.Supplementary file1 (DOCX 25 KB)Supplementary file2 (PPTX 9266 KB)Supplementary file3 (DOCX 144 KB)Below is the link to the electronic supplementary material.


During the COVID-19 pandemic, the use of non-invasive respiratory support (NIRS) became crucial in treating patients with acute hypoxemic respiratory failure. Despite the fear of viral aerosolization, non-invasive respiratory support has gained attention as a way to alleviate ICU overcrowding and reduce the risks associated with intubation. The COVID-19 pandemic has led to an unprecedented increased demand for research, resulting in numerous publications on observational studies, clinical trials, reviews, and meta-analyses in the past three years. This comprehensive narrative overview describes the physiological rationale, pre-COVID-19 evidence, and results of observational studies and randomized control trials regarding the use of high-flow nasal oxygen, non-invasive mechanical ventilation, and continuous positive airway pressure in adult patients with COVID-19 and associated acute hypoxemic respiratory failure. The review also highlights the significance of guidelines and recommendations provided by international societies and the need for further well-designed research to determine the optimal use of NIRS in treating this population. Since the onset of the COVID-19 pandemic in January 2020, there has been a rise in acute respiratory distress syndrome (ARDS), a well-recognized entity and one of the virus’ main life-threatening complications . The benInterest in NIRS grew as ICU resources became limited. They were one of the first-line strategies to avoid the risk of ICU overcrowding, as they could also be used in emergency departments, monitored beds, and sometimes general wards. The high mortality observed in patients undergoing invasive mechanical ventilation drew even more attention to NIRS, which avoids the risks and complications associated with intubation and invasive mechanical ventilation .NIRS was a frequent therapeutic choice for patients with COVID-19-related acute respiratory failure, particularly those that requested “no intubation”  and in tWe conducted a review of the literature using the PubMed and Google Scholar databases to provide an up-to-date overview of the research on NIRS during the early pandemic (2019–2022). Studies were included if they focused on evidence from the pre-COVID-19 era regarding the physiology associated with the use of NIRS  and its rationale for its use for treating patients that develop acute respiratory failure due to COVID-19. The results are presented as a narrative review, where the selection of content is based on the author’s experience, the study type, and the date of publication, including observational studies, clinical trials, reviews, and published guidelines. The evidence and clinical recommendations are summarized in three main sections: physiology and pre-COVID-19 era, observational studies, and clinical trials.2) ranging from 21% to 100%   . At the = 0.055] . The res= 0.055] . Even wh= 0.055] . Another= 0.055] . In the = 0.055] . As form= 0.055] , the use= 0.055] . In September 2021, a Korean observational study reported that late failure of HFNO, defined as the need for invasive mechanical ventilation after 48 h of treatment, was associated with higher mortality in COVID-19 patients compared to early failure (within 48 h) . HoweverDespite these encouraging results, concerns have been raised about the risk of viral aerosolization and spread . SeveralIn conclusion, practical measures such as proper personal protective equipment, correct placement of nasal cannulae, and the low rate of viral contamination reported in observational studies should encourage more confident use of HFNO. HFNO use in clinical practice has also been supported by cohort studies, which report a reduced need for intubation and subsequent invasive mechanical ventilation with no apparent effect on mortality.2/FiO2 < 200), who were randomized to receive either helmet NIV or HFNO  or PEEP) and the inspiratory pressure (inspiratory positive airway pressure [IPAP]). When the inspiratory effort is detected, NIV delivers inspiratory assistance pressure support using a decelerated flow, keeping IPAP constant, and allowing clinicians to control and improve ventilation . High inCPAP is a NIRS strategy that is provided via a mask connected to a simple airflow/oxygen source, generating a continuous positive pressure over the airway and lungs ,97,98. DIn patients with COVID-19 acute respiratory failure, NIV and CPAP can have positive effects when the patient selection is appropriate. However, care must be taken to avoid harm derived from delayed intubation and excessive respiratory effort. Studies have shown that NIV and CPAP can reduce significantly esophageal pressure and improve oxygenation without demonstrating a difference in dynamic transpulmonary driving pressure compared to HFNO  . CPAP maDespite the high demand for respiratory support and a shortage of resources to manage the increasing number of patients with acute respiratory failure, the use of NIV for COVID-19 patients was not widely adopted. This was mainly due to concerns about delayed intubation, P-SILI virus, and virus transmission through aerosol generation, the latter being a major concern . 2/FiO2 ratio ranging from 52 to 126.7 [2/FiO2 ratio was similar for those receiving NIV and those receiving invasive mechanical ventilation [NIV was used early in the COVID-19 pandemic. The first report of its use was from a retrospective observational study in China (December 2019), which found that 29 of the 52 critically ill adult patients with COVID-19 pneumonia admitted to ICU received NIV (56%) . Sixty-sto 126.7 . Thirty to 126.7 . Similarto 126.7 . Of the tilation . Nevertheless, the NIV use varied greatly among countries. Only 4% (4 out of 225 patients) of COVID-19 patients admitted to Australian intensive care units in the early pandemic received NIV on their first day at the ICU . SimilarSince NIV and CPAP are listed by the World Health Organization as high-risk aerosol-generating procedures, one of the concerns that limited the use of NIV or CPAP in the early reports was the airborne risk for patients and healthcare workers ,111,112.2/FiO2 ratio ranged from 97 to 175, and the median time to intubation was just 4 h, which contrasts with other studies reporting a median of 1 day until intubation [2/FiO2 ratio ≤ 100, should not wait for invasive support. Starting NIV/CPAP in patients with ARDS in the moderate stage (PaO2/FiO2 ratio between 100 and 200) has been associated with a reduction of both in-hospital mortality and hospitalization length compared to the severe stage; meanwhile, starting NIV or CPAP with a PaO2/FiO2 ratio > 150 will not present any clinical advantage [To ensure the safe use of NIV or CPAP, special units or teams outside the ICU were established. Nightingale et al. reported the use of CPAP to treat hypoxemic respiratory failure due to COVID-19 in negative pressure rooms in a new infectious disease unit . A case tubation . Delayintubation . Patientdvantage .The use of NIRS, specifically Bilevel-NIV/CPAP, continued to have growing evidence in 2021 with systematic reviews suggesting high heterogeneity among studies. Only 3 out of 17 studies were prospectively conducted, highlighting the need for well-designed clinical trials ,116,117.The first RCT examining the use of NIV for COVID-19 patients with acute hypoxemic respiratory failure was the HENIVOT trial, published in May 2021 . It invoThe third randomized clinical trial was the RECOVERY-R, which was published in 2022, and compared CPAP or HFNO with conventional oxygen therapy and was conducted between April 2020 and May 2021. The trial was stopped prematurely due to declining COVID-19 cases, but still included 12,673 patients. The results showed a lower tracheal intubation rate with CPAP  versus conventional oxygen therapy , but there was no significant difference with HFNO  and conventional oxygen therapy  [A recent randomized clinical trial from September 2022 suggested that helmet NIV did not have a significant impact on reducing 28-day mortality compared to standard respiratory support in patients with acute hypoxemic respiratory failure caused by COVID-19 pneumonia . HoweverIn summary, according to the guidelines , CPAP/NINIRS gained importance during the COVID-19 pandemic due to its reduced risk of complications and its ability to alleviate ICU overcrowding. Although the use of HFNO has shown a reduced need for intubation and subsequent invasive mechanical ventilation with no apparent effect on mortality, CPAP (delivered through either a helmet or a facemask) may offer some clinical benefits over HFNO, and NIV could offer some advantages in patients with more severe oxygenation impairment and intense inspiratory effort.Clinical judgment, caregiver expertise, and resource availability remain key determinants in the use of NIRS in treating COVID-19 patients with acute respiratory failure. Research on NIRS in COVID-19 acute respiratory failure has dramatically increased, but further confirmation of its benefits and potential complications through larger trials is still needed, especially due to concerns about delayed intubation, virus transmission, and P-SILI.


This study aimed to investigate microglial and macrophage activation in 17 patients who died in the context of a COVID-19 infection in 2020 and 2021.Through immunohistochemical analysis, the lysosomal marker CD68 was used to detect diffuse parenchymal microglial activity, pronounced perivascular macrophage activation and macrophage clusters. COVID-19 patients were compared to control patients and grouped regarding clinical aspects. Detection of viral proteins was attempted in different regions through multiple commercially available antibodies.Microglial and macrophage activation was most pronounced in the white matter with emphasis in brain stem and cerebellar areas. Analysis of lesion patterns yielded no correlation between disease severity and neuropathological changes. Occurrence of macrophage clusters could not be associated with a severe course of disease or preconditions but represent a more advanced stage of microglial and macrophage activation. Severe neuropathological changes in COVID-19 were comparable to severe Influenza. Hypoxic damage was not a confounder to the described neuropathology. The macrophage/microglia reaction was less pronounced in post COVID-19 patients, but detectable i.e. in the brain stem. Commercially available antibodies for detection of SARS-CoV-2 virus material in immunohistochemistry yielded no specific signal over controls.The presented microglial and macrophage activation might be an explanation for the long COVID syndrome. In January 2020, Zhu et al.  sequenceAlthough COVID-19 is largely considered a respiratory infection, neurological symptoms are fairly common: Pathognomonic early signs of infection are anosmia and ageusia , 3. MildThe pathophysiology on how SARS-CoV-2 induces neurological symptoms is not well understood: Main competing hypotheses are neurotropism or effects mediated by the virus-induced cytokine storm .Neuropathological findings in COVID-19 autopsies include microgliosis, astrogliosis, inflammatory infiltrates, hypoxic–ischemic lesions, edema and hemorrhagic lesions . The detThis study aimed to investigate microglial and macrophage activation in 17 patients who died in the context of a COVID-19 infection in 2020 and 2021 through immunohistochemical analysis.The lysosomal marker CD68 was used to detect the broad immune response to inflammatory processes in the brain. It is expressed by all cell lines of the mononuclear phagocyte system: meningeal macrophages, macrophages that migrated through bloodstream and activated phagocytizing microglia. Inflammatory glial and macrophage response was evaluated in distribution and intensity and compared to SARS-CoV-2-negative control patients.Detection of viral proteins was attempted in different regions through multiple commercially available antibodies.n = 17) who had died between April 2020 and June 2021 following a confirmed SARS-CoV-2 infection were autopsied at the Saarland University Medical Center . Main inclusion criterion for this study was a confirmed diagnosis of SARS-CoV-2 infection via quantitative RT-PCR during lifetime. Clinical presentation was not considered for inclusion in this study. For comparison of inflammatory microglial and macrophage response, a control group of patients (n = 5) was autopsied that was not infected with SARS-CoV-2. Additionally, specimen of 12 control patients that died before 2020 was used as negative controls for the immunohistochemical detection of SARS-CoV-2 antigens. Health records of each patient were reviewed to gather information about comorbidities and hospitalization history. Basic characteristics of patients are summarized in Patients  blocks were taken. The sampling sites were gyrus frontalis medius, gyrus cinguli, gyrus parietalis inferior, area striata, anterior striate, basal ganglia, amygdala, thalamus, hippocampus, cerebellar vermis, cerebellar hemisphere, mesencephalon, pons, medulla oblongata and trigeminal ganglion.Hematoxylin–eosin (HE) staining according to standard procedures and immunohistochemical staining were performed on 1–3-μm-thick FFPE tissue sections.2O2 for 10 min (20 min for CD68) at room temperature either prior  or after heat antigen retrieval. Immunohistochemical stainings were performed using the coverplate system (Thermo Fisher Scientific) and a Dako staining kit. Sections were subsequently incubated for 45 min at room temperature with the primary antibody. The primary antibodies and specific pretreatments used for detecting microglia/macrophage activity and SARS-CoV-2 antigens are summarized in Sections were deparaffined and rehydrated. Heat antigen retrieval was performed by steaming at 98°C in target retrieval solution (TRS) pH 6.1  for 30 min or pH 9  for 15 min. Sections were then allowed to cool down. Peroxidases were blocked by incubation in 1% HAll antibodies were diluted in Dako REAL antibody diluent . Following three washes with wash buffer , 3-amino-9-ethylcarbazol (AEC) was used for visualization of the antibody reaction in the case of CD68- and SARS-CoV-2-related primary antibodies. For all other immunohistochemical procedures the Dako REAL EnVision HRP kit (Cat.-No. K5007) was used according to the manufacturer’s instructions. Using both methods, brown staining was rated as a “positive signal.” Sections were then counterstained with Mayer’s haemalum , mounted and coverslipped.HE and immunohistochemistry sections were evaluated by one board-certified neuropathologist and one medical student with concurrence.First, an orienting histomorphological assessment was carried out on the HE stained sections. Subsequently, CD68-immunoreactivity was assessed. Slides were screened at low magnification and areas with the most pronounced changes were used for quantification. Two distinct patterns were observed: the presence of diffuse parenchymal microglial activation and the presence of perivascular macrophage activation. A semiquantitative categorization, similar to the grading of Yang et al. . Range of possible NP lesion score values is 0 to 6. Areas with the most pronounced changes compared to control patients were selected for graphical illustration. Groups were composed according to clinical variables. Ten areas were chosen for characterizing the lesion pattern in the brain of COVID-19 patients: the white matter of the medial frontal gyrus, the white matter of the anterior cingulate gyrus, the putamen at the level of the anterior striate, the amygdala, the white matter besides the hippocampus at the level of the lateral geniculate, the white matter of the cerebellar hemisphere, the cerebellar nuclei, the white matter of the pons, pontine nuclei and the pyramidal tract at the level of the midbrain. With the regions on the x-axis, line charts were plotted with the mean value and the range of grading scores for each analysis. For group composition, various clinical aspects were applied to determine influencing factors.Statistical analysis and graphical illustration were performed using Microsoft Excel (version 16.57).The evaluation of all 17 COVID-19 patients versus control patients yielded three distinct pattern which were present throughout the COVID-19 patients: diffuse parenchymal microglial activity, pronounced perivascular macrophage activation and macrophage clusters . These patients were critically ill according to the National Institutes of Health’s Covid-19 treatment guidelines . RemainiAnalysis of lesion patterns yielded no obvious association between disease severity and neuropathological changes (illustrated in n = 8), most often in white matter areas of the cerebrum (n = 6) followed by the white matter of the brain stem (n = 5), the internal capsule/pyramidal tract (n = 3) and the cerebellar white matter (n = 1). Clusters were also frequently observed in the nuclei of the brain stem (n = 4), the basal ganglia (n = 1) and in the cerebellar nuclei (n = 1). Occurrence of clusters could not be associated with a severe course of disease.CD68-positive clusters were detected in 10 patients , representing 59% of analyzed COVID-19 autopsies. Clusters in the white matter were most frequent , who was ventilated for 38 days, to six COVID-19 patients  that were ventilated for an average period of 32 days. Like most of the selected COVID-19 patients, control patient 1 suffered a septic shock.Analysis of lesion patterns suggests that neuropathological changes in severe COVID-19 are comparable to severe Influenza  of analyzed COVID-19 patients was hypoxic damage, frequently diagnosed through neuronal cell death in the CA1 region of the hippocampus. Hypoxic COVID-19 patients  were compared to the rest of the cohort  analyzed cases, while only one patient harbored SARS-CoV-2 viral proteins in the brain tissue , which seem to have neurotropic and neuroinvasive capabilities . AnotherIn the present study we analyzed specimen from 17 COVID-19 patients. Comparing our cohort to sample sizes in systematic reviews from Maiese et al.  21 pape (45 papeWe chose immunohistochemistry to both detect protein structures and gain information on their anatomical localization, compared to the sole detection of RNA molecules by PCR.When using postmortem specimen for immunohistochemistry, influencing factors such as autolysis and insufficient formalin fixation must be considered. It is possible that some epitopes were masked and therefore not detected by antibodies , 41. EpiDue to limited clinical data, correlation of neuropathological findings to patient history, especially development of neurological symptoms, was only partially possible. However, quality and quantity of data is comparable to other studies . Due to Since specimen collection ended in June 2021, results of this study can only be applied to the original SARS-CoV-2 variant. Neuropathological lesions in patients infected with the omicron-variant of SARS-CoV-2 might differ.As in all autopsy-based studies, described pathology refers to the most severe cases . Our cohCOVID-19 is not just a respiratory infection. Neurological symptoms of acute infection and “post-COVID” can hypothetically be explained by neuropathologic findings. We presented enhanced microglial and macrophage activity in the white matter, cerebellum and brain stem throughout patients, regardless of disease severity or neurological clinic. Microglial and macrophage activation also remained elevated in “post-COVID” patients. Like most published papers on the subject, we could not verify the presence of SARS-CoV-2-specific antigens in the brain.Results of this study highlight the necessity to continue research on “long COVID” symptoms and pathophysiology, as SARS-CoV-2 variants become endemic and seropositivity increases.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Saarland Chamber of Physicians. The patients/participants provided their written informed consent to participate in this study.WS-S, JS, and MK provided and organized tissue samples. WS-S administrated and supervised the project, provided the resources, captured images, reviewed, and edited the original draft. JS performed immunohistochemical and HE stains, wrote the original draft, and created visualizations. MK performed immunohistochemical stains. WS-S and JS performed microscopic analysis. SS provided data, reviewed, and edited the manuscript. All authors have read and approved the manuscript.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.


This study aimed to evaluate the incidence, severity and presence of symptoms of respiratory tract infections and COVID-19, in patients with pre-existing thyroid dysfunction compared to individuals without thyroid diseases, during the peak month of the COVID-19 pandemic in the Netherlands.In this retrospective observational cohort study, all patients currently under follow-up at the Radboud UMC for thyroid dysfunction received a digital questionnaire. Primary outcomes were incidence of self-reported sickness and cases diagnosed with COVID-19. We compared these primary outcomes between these patients and individuals without thyroid diseases that received the same questionnaire, recruited from the Human Functional Genomics Cohort at the Radboud UMC.In total, 238 patients with pre-existing thyroid dysfunction and 161 controls were included. Patients did not report more sickness  or microbiologically confirmed SARS-CoV-2 infections . COVID-19 clinical diagnosis was more frequently made in patients with thyroid diseases , despite overall lower incidence of self-reported respiratory related symptoms , compared to controls. Sub-group analysis between patients with autoimmune and not-autoimmune thyroid dysfunction did not reveal significant associations with respect to any of the outcome measures.This retrospective survey of a cohort of patients with from a tertiary academic hospital suggests that pre-existing thyroid dysfunction, independent from the aetiology, does not lead to an apparent risk to develop respiratory tract infections and COVID-19 related symptoms. COVID-19 is caused by the ‘severe acute respiratory syndrome coronavirus 2’ (SARS-CoV-2) . Zheng aImmune responses required for adequate defence against infections are tightly regulated by numerous signals from the nervous and endocrine systems, including thyroid hormones –9. MoreoThyroid diseases are some of the most prevalent endocrine diseases . The maiThe present study aims to evaluate the incidence, severity and presence of symptoms of respiratory tract infections, with a specific focus on SARS-CoV-2, in a cohort of patients with pre-existing thyroid diseases causing thyroid dysfunction, during the first peak of the COVID-19 pandemic in the Netherlands. Questionnaire data from the thyroid cohort was compared to data from individuals without thyroid conditions who received the same questionnaire to assess the possible different risk factors that contribute to respiratory tract infections.All patients currently under follow-up at the Radboud University Medical Centre (Radboud UMC) for a thyroid disease causing thyroid dysfunction were approached (n = 369). Exclusion criteria included: insufficient understanding of Dutch language and altered health status that did not allow them to participate. In the patient group, 10 patients reported using the following potentially immunosuppressive medication: prednisolone (two patients), methotrexate (two patients), adalimumab (one patient), etanercept (one patient), vedolizumab (one patient), tocilizumab (one patient), certolizumab (one patient), and imatinib (one patient).The control cohort consisted of 460 apparently healthy individuals from the same geographic region (Nijmegen) without known thyroid diseases who were recruited from one of the Human Functional Genomics Cohorts at the Department of Internal Medicine of the Radboud UMC (500FG cohort) . ParticiThis study was approved by the Research Ethics committee at the Radboud UMC Nijmegen, the Netherlands and was performed in accordance with the principles expressed in the Declaration of Helsinki. All participants gave written informed consent for inclusion in the study.Primary outcome measures were self-reported sickness, defined as “any illness that led to absenteeism from work or prevented the individual from performing activities outside the house” , and conwww.castoredc.com). Questionnaire data from the control cohort had been gathered previously for the purpose of another study  as main predictor, next to the possible confounders of age, presence of comorbidities (none/one or more), medication use (none/one or more), healthcare-work (yes/no), known contact with COVID-19 patients (yes/no), and international travel during the study period (yes/no). As we observed a difference in the duration of sickness between the two cohorts, we next aimed to assess what predictors would underlie this difference, such as age, autoimmune thyroid disease (yes/no), current thyroid function status, presence of comorbidities (none/one or more), use of medication (none/one or more) and BMI, which are known potential risk modifiers. Data are shown as mean (±SD) and absolute numbers (percentage). The level of significance was set as a two-tailed p < 0.05.vs. 35.6 years; p < 0.001), more frequently female , and more of them had comorbidities (p < 0.001) or used medication (p < 0.001) compared to the controls. They also reported less international traveling during the study period (p = 0.001), less frequently worked in the healthcare industry (p < 0.001) and were more frequently unemployed (p < 0.001) compared to the controls. Of the patients, 71 (29.8%) had an autoimmune thyroid disease. At the time of assessment, only 14.3% had clinically manifest hypo- or hyperthyroidism  completed the questionnaire. In the control group, of the 460 volunteers who were sent the questionnaire, 207 (45%) responded. Of these, 44 were excluded because they had been vaccinated with BCG, and 2 because they used levothyroxine. Finally, 161 individuals were included in the control group. The study populations’ characteristics are shown in yroidism . Of the vs. 0.6%, p = 0,351), but the patients were more frequently clinically diagnosed with COVID-19 by a physician . No hospital or ICU admissions were reported in either of the cohorts.Among the patients, 73 (30.7%) reported sickness for 1 or more days, compared to 47 controls , although upon investigating the specific symptoms separately, the patients more frequently reported having chills compared to the controls  , or more confirmed  or suspected SARS-CoV-2 infections  than the control cohort. However, patients with thyroid carcinoma less frequently reported COVID-19-related symptoms compared to individuals in the control cohort .Among the patients, no differences were found between those with autoimmune or non-autoimmune disease for any outcome measures shown in . FurtherThe logistic regression model fit created to adjust for possible confounding factors for a correlation between thyroid dysfunction and reported sickness was appropriate (p = 0.616) and showed an AOR of 0.984  for age.vs. 5.5 days, p = 0.001; shown in The patients reported a longer mean duration of sickness than the controls , and thus the parameter of clinical symptoms is likely to have been non-specific.The patients reported a prolonged duration of sickness compared to the controls. Unfortunately, our linear regression model adjusting for possible confounders was unable to confirm this difference, although we hypothesize the lack of power could have caused this because the sub-group analysis included only 128 participants who reported sickness.Several limitations should be considered. First, because of the study's retrospective nature and the fact that it was based on self-reported information, recall bias cannot be ruled out. Second, due to the small size of the subgroups of patients with different thyroid diseases, we cannot exclude how this study lacked the statistical power to analyse the effects of different thyroid dysfunction aetiologies. Third, because of the pandemic's quickly changing dynamics, data for the two cohorts covered a slightly different, though largely overlapping, period. This may have led to differences in the incidence of the self-reported data. Furthermore, although conclusions on the incidence of confirmed SARS-CoV-2 infection are valid, some of the infected patients and controls may not have been tested because they did not fulfil the case definition at that time. Therefore, the true incidence of SARS-CoV-2 infections is likely underestimated. Another limitation regards using potentially immunosuppressive medication in 10 patients, which could have modified the risk for the disease. However, the linear regression analysis did not reveal a significant effect of the use of medication on the study's main outcome. Moreover, the study population does not reflect the epidemiological data of the general population with thyroid dysfunction, rather it reflect the selected population currently under treatment and follow-up at our tertiary academic centre, including patients with more complex endocrine problems.In conclusion, this is the first study on self-reported respiratory tract and SARS-CoV-2-related complaints and infection rates during the COVID-19 pandemic in patients with pre-existing thyroid dysfunction. Despite its potential limitations inherent to the retrospective nature of this questionnaire study, these data show that pre-existing thyroid dysfunction, regardless of aetiology, does not lead to an apparent risk to develop respiratory tract infections and COVID-19-related symptoms. Nonetheless, a modified susceptibility to SARS-CoV-2 infection cannot be completely ruled out. Future studies including larger sub-groups of patients with different thyroid diseases and more accurate confirmation of the infection should be conducted to provide more insight into the risk factors of COVID-19 in patients with pre-existing thyroid dysfunction.


Previous clinical studies have found that negative mental states such as depression and anxiety are closely related to COVID-19 infection. We used Mendelian randomization (MR) to explore the relationship between depression, anxiety, and COVID-19 infection.Our data were based on publicly available GWAS databases. The COVID-19 samples were obtained from the COVID-19 Host Genetics Initiative (HGI). The depression samples were obtained from the Psychiatric Genomics Consortium (PGC). The anxiety samples were derived from the Finngen database. We used inverse-variance weighting (IVW) as the primary analysis method, with weighted median, MR Egger, and multivariate MRI adjustment.There was no causal effect of different COVID-19 infection statuses on depression and anxiety as determined by MR analysis. In addition, in the reverse MR analysis, we found a significant causal effect of anxiety on severe symptoms after COVID-19 infection. The results of the MR Egger regression, weighted median, and weighted mode methods were consistent with the IVW method. Based on sensitivity analyses, horizontal pleiotropy was unlikely to influence the final results.Our findings indicate that anxiety is a risk factor for severe symptoms following COVID-19 infection. However, the mechanism of interaction between the two needs further investigation. From 2019 to 2022, COVID-19 spread worldwide, causing severe public health issues on a global scale. It is an infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), with an estimated 2.75 billion persons at risk of infection .The main symptoms of COVID-19 sequelae include shortness of breath, cognitive dysfunction, fatigue, anxiety, and depression . CompareDepression is a prevalent mental illness that affects many individuals. In clinical practice, the most common symptoms are a depressed mood, a lack of interest, and impaired cognitive function . AccordiGenetic factors significantly influence the susceptibility to and the severity of a wide range of infectious diseases and psychiatric disorders. Several recent studies have found the same genetic factor linking psychiatric disorders and infectious diseases. The presence of numerous SNP sites on the HLA gene associated with psychiatric disorders and mutations in these sites may affect the immune response to foreign antigens, which may account for the increased incidence of infections and inflammation in patients with schizophrenia and bipolar disorder and their parents . A largeMendelian randomization (MR) is an epidemiological research technique that uses genetic variants as instrumental variables to infer the causality of a risk factor because it employs genetic variants as instrumental variables , 16. MenWe hereby briefly describe the design of the bidirectional MR between COVID-19 and depression/anxiety. Using pooled data from genome-wide association studies (GWAS), we performed two MR analyses to examine bidirectional associations between various COVID-19 statuses and depression/anxiety. Reverse MR analyses used depression/anxiety as exposure and distinct COVID-19 statuses as outcomes. (1) There is a substantial association between genetic variation and exposure.(2) Genetic mutations are unrelated to other confounding variables.(3) Only exposure is associated with genetic variation and outcome.Based on summary statistics available to the public, this research did not require ethical approval.We attempted to perform MR analysis using the COVID-19 GWAS data. The COVID-19 dataset was obtained from the COVID-19 Host Genetics Initiative (HGI). GWAS provided us with the association between COVID-19 and COVID-19 genetic associations of phenotypes. The GWAS yielded three phenotypes: (1) COVID-19 patients and the general population ; (2) hospitalized COVID-19 patients and the general population ; and (3) patients with severe respiratory confirmed COVID-19 and the general population  . Depressp < 5 × 10−8)  . To ensuariables , 26. We Using a random-effects inverse variance weighting (IVW) method, we estimated the bidirectional causality between COVID-19 status and depression/anxiety. The IVW method presupposes that all MR assumptions are legitimate. However, IV influenced the results through other pathways, indicating that horizontal pleiotropic effects may exist and that estimates of IVW causality may be biased. Therefore, we conducted sensitivity analyses utilizing the MR Egger and weighted median methodologies, allowing us to estimate causality accurately even in the presence of invalid SNPs.2, which indicates the proportion of the exposure variable's variation that can be explained by genetic variation. We calculated the f-statistics to evaluate the instrumental intensity of the relationship between IV and interest exposure risk. F represents weak instrumental vigor. MR Egger regression intercepts and their respective 95% confidence intervals (CIs) were utilized to examine the extent to which directional pleiotropy, which precludes limiting assumptions, leads to bias in arbitrary estimates. Moreover, horizontal pleiotropy was evaluated using the Mendelian randomized pleiotropy residuals and outliers (MR-PRESSO) global test, and the outlier SNPs were excluded using the MR-PRESSO outlier test. Additionally, after removing the peripheral IV, we examined whether there was a statistically significant difference between the new IV and the previous one. Using Cochran's Q statistic and funnel diagrams, we also examined the IVW and MR Egger methods for heterogeneity. Then, various sensitivity analyses  were conducted to determine whether individual SNPs affected primary causality. Using odds ratios (OR) and 95% confidence intervals (CIs), we estimated causality for binary outcomes. We presented causal estimates, p-values, and their standard errors for both binary and continuous outcomes. Each p-value is bilateral. All analyses were conducted utilizing the R  TwoSampleMR and Mendelian randomization packages.As MR relies on the three central IV assumptions of the primary analysis , we herep < 5 × 10 −8, r2 < 0.001, kb = 10,000) for exposure. However, anxiety was adjusted to a significance threshold of p < 5 × 10 −6 because only a few SNPs were acquired. Detailed data are provided in We obtained 51 SNPs as instrumental variables in depression, 54 in anxiety, 29 in very severe respiratory confirmed COVID-19, 33 in COVID-19 hospitalization COVID-19 SNPs, and 15 SNPs in COVID-19 infection, which met the generally accepted genome-wide significance threshold (P = 0.95) and depression . Similarly, COVID-19 requiring hospitalization exhibited no significant relation to anxiety  and depression , while COVID-19 infection also presented with no significant association with anxiety  and depression . Further analyses using MR Egger regression, weighted median, and weighted mode methods continued to show no causal association between different COVID-19 infection statuses and depression/anxiety. Detailed information can be found in As shown in P = 0.06), depression for hospitalized COVID-19 , and depression for COVID-19 . Anxiety for very severe respiratory confirmed COVID-19 , anxiety for hospitalized COVID-19 , and anxiety for COVID-19 .We further validated the relationship between different COVID-19 infection statuses and depression/anxiety using directional MR. As shown in In this study, we explored whether there is a causal relationship between COVID-19 infection and anxiety/depression. As described in the results, we found that there does not appear to be a highly significant causal link between COVID-19 infection and anxiety/depression. Only anxiety disorders were causally associated with severe reactions after COVID-19 infection, and anxiety disorders may be a risk factor for severe illness after COVID-19 infection.Previous observational clinical studies have found that more than 50% of the infected patients have depression or anxiety-like symptoms after COVID-19 infection, and anxiety and depression are also the typical symptoms of COVID-19 sequelae considered by the WHO , 28. In During the COVID-19 pandemic, many individuals have been required to maintain a safe distance from one another to prevent the spread of COVID-19, resulting in social isolation . It is bIntensive research on inflammation and psychiatry suggests that immune system perturbations triggered by infection may specifically promote psychopathology, increasing the psychological stress of living with a potentially fatal illness and stress-related inflammation . InteracMental factors such as depression and anxiety are important risk factors for many diseases, such as cardiovascular diseases, digestive tract diseases, and susceptibility to viruses , 51. OurThe very interesting finding in our study is that anxiety seems to be a risk factor for developing severe illness after a COVID-19 infection. However, depression does not seem to increase the risk of developing severe illness after COVID-19 infection. Anxiety disorders are often accompanied by autonomic arousal compared to depression . In addiHowever, the results regarding the causal relationship between anxiety and the risk of severe illness after COVID-19 infection do not seem to be strong. Meanwhile, a large number of clinical studies have shown that a poor psychological state prior to COVID-19 infection is a key factor in triggering severe COVID-19 disease after infection . Chen etThis study also has some limitations. First, the data we selected were from a European population lacking generalizability. We also needed more specific raw data for subgroup analyses. In future studies, we will increase the sample size, expand the population to include different ethnic groups, and collect appropriate subgroup information for more in-depth analyses.We used a much broader population sequence than in previous studies. Our study identified anxiety disorders as a risk factor for the development of severe symptoms following COVID-19 infection. Patients with anxiety disorders are more likely to have severe symptoms after COVID-19 infection than the general population. Although this association does not appear to be strong, given that anxiety disorders are risk factors for a wide range of diseases, we should pay more attention to people with anxiety disorders during future infectious disease pandemics.The original contributions presented in the study are included in the article/LZ and ZH conceived the idea for this study. LZ, GS, and SJ obtained genetic data and performed data analysis. LZ and SJ were responsible for revising the article. CX and LY explained the results of the data analysis. ZH wrote the article. All authors approved the submitted version.


Objectives: Opioid-free anesthesia with erector spinae plane block (ESPB) has the potential to decrease perioperative opioid need, thereby potentially reducing related complications. This study aimed to compare opioid-free anesthesia with ESPB and standard opioid-based balanced anesthesia in patients undergoing video-assisted thoracic surgery (VATS) in terms of postoperative opioid need  as well as postoperative pain management, recovery quality, and opioid-related side effects.Methods: Seventy-four patients, ranging in age from 18 to 75 years, who underwent lobectomy with VATS were included in this randomized-controlled study. The opioid-free group had ESPB, and no opioid was used during anesthesia maintenance. The opioid group received standard anesthesia with opioid use. Postoperative morphine requirement, postoperative pain as measured by the visual analog scale (VAS), intraoperative vital parameters, recovery quality using the Quality of Recovery-40 (QoR-40) questionnaire, and opioid-related complications were compared between groups.Results: The opioid-free group received a significantly lower total dose of morphine during the first 24 postoperative hours through patient-controlled analgesia (PCA) when compared to the opioid group . In addition, the opioid-free group had significantly better postoperative pain scores and QoR-40 scores , shorter times to mobilization , and oral intake , as well as less frequent opioid-related side effects.Conclusion: The findings of this study suggest that opioid-free anesthesia with ESPB represents a promising option for patients undergoing lobectomy with VATS. It has the potential to decrease postoperative opioid need, improve postoperative pain management, and reduce opioid-related unwanted consequences. Neuropathic pain following video-assisted thoracic surgery (VATS) is still an important postoperative problem, although it is less marked when compared to the thoracotomy approach . Pain maUltrasound-guided erector spinae plane block (ESPB) is a recently defined regional anesthesia technique where local anesthetic is injected into the erector spinae muscle and fascial plane and the agent is allowed to diffuse in caudal and cranial directions. This technique has been successfully used in thoracic surgery and trauma, breast surgery, abdominal surgery, and extremity surgery for the purpose of intraoperative regional anesthesia as well as postoperative analgesia . RegionaThis study aimed to compare opioid-free anesthesia with the aid of ultrasound-guided ESPB with standard anesthesia with opioid use in patients undergoing lobectomy with VATS in terms of postoperative opioid need and pain management, recovery quality, as well as opioid-related complications.PatientsClinicalTrials.gov).Forty-eight male and 29 female patients who are 42-70 years old with ASA (American Society of Anesthesiologists) physical status ≤3 who underwent lobectomy with VATS and provided informed consent for study entry were included in this randomized-controlled study. Patients with contraindications to either of the anesthesia methods, chronic pain, allergy to local anesthetics, spinal deformity, mental or psychiatric problems preventing cooperation, as well as patients using opioids or anticoagulants were excluded from the study. Randomization was carried out at a ratio of 1:1 using the closed-envelope method. Random allocation cards were made using computer-generated random numbers and placed in sealed envelopes . Before the procedure, a sealed envelope was opened by the anesthesiologist in the operating room, and the procedures were performed according to the group specified in the paper, either an opioid-free anesthesia group or an opioid-based anesthesia group. In addition, the following patients were not included in the analyses: patients in whom ESPB was unsuccessful; patients who required opioids during the procedure (for the opioid-free group); and patients requiring a switch to open surgery (for both groups). This study was approved by the local ethics committee, and all patients gave written informed consent prior to study entry. The study was conducted in accordance with the ethical standards of the institutional ethics committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethical approval: This study was approved by the ethics committee of the Marmara University Faculty of Medicine . Trial registration: NCT05321576 , all patients were monitored with the bispectral index (BIS) and the Analgesia Nociception Index (ANI). ANI and BIS were monitored to objectively evaluate perioperative pain and anesthesia depth, respectively. Anesthesia management was provided with the same volatile agent, sevoflurane, in both groups, with added intravenous remifentanil infusion in the "opioid group," and intravenous dexmedetomidine infusion in the "opioid-free group." The infusion rate of remifentanil and dexmedetomidine was titrated to keep ANI monitoring values between 50 and 70. The BIS value was targeted in the range of 40 to 60. Table Opioid-free anesthesia group (with ESPB)Before induction of anesthesia, ESPB was carried out on one side (at the side of the operation) by an experienced anesthesiologist in a sitting position and under ultrasound guidance. The injection site was identified at 3 cm lateral to the T5 spinous process, and injection was done using the in-plane technique. The needle was advanced in a cranio-caudal direction, and 1-2 ml of saline was injected to separate the erector spinae muscle from the transverse process. Following the separation, 20 ml of 0.5% bupivacaine and 100 mg (5 ml) of lidocaine were injected. No analgesic or sedative was used during the procedure. Anesthesia was induced with propofol (2 mg/kg), ketamine (2 mg/kg), and rocuronium (0.6 mg/kg). This group did not take any opioids during the operation but instead received continuous dexmedetomidine infusion at an initial dose of 0.4 µg/kg/h, and the dose was adjusted to keep the BIS value between 40 and 60 and the ANI between 50 and 70.Opioid anesthesia groupAnesthesia was induced with propofol (2 mg/kg), remifentanil (1 µg/kg), and rocuronium (0.6 mg/kg). This group received continuous remifentanil infusion with an initial dose of 0.5 µg/kg/h, and the dose was adjusted to keep BIS <50 and ANI >50 throughout the operation. After the surgical procedure was completed before awakening, both groups received intravenous 1 g of paracetamol.Assessments2), BIS, and ANI.Groups were compared in terms of study outcomes. The primary outcome was postoperative morphine requirement (during the first and second 24 hours). Secondary outcomes were as follows: postoperative pain , need for rescue analgesia, anesthesia-related complications, indicators for postoperative recovery , and changes in intraoperative measurements including heart rate (HR), mean arterial blood pressure (MAP), oxygen saturation , where 4 mg of morphine was self-delivered by the patient with each application with a lockout time of 15 minutes. When necessary, rescue analgesia (tramadol or paracetamol) was provided. Morphine doses and rescue analgesia needs were recorded. Immediately after awakening and at 6, 12, 24, and 48 postoperative hours, the pain was evaluated using a 10-point VAS.Statistical analysisSample size estimation revealed that a total of 33 patients per group would be necessary to detect a mean difference of at least 2.5 mg in morphine equivalent consumption within the first 24 hours between the two treatment groups, with an alpha error of 0.05 and a beta value of 0.1 (power = 0.9). Considering the 10% dropout rate, the inclusion of 37 patients in each group was planned. For data analysis, Statistical Package for Social Sciences (SPSS) version 21 software  was used. The normality of continuous variables was tested using graphical methods and hypothesis tests. Between-group comparisons of continuous variables were done using the student t-test for independent samples or the Mann-Whitney U test, depending on the data distribution. The Pearson chi-square test or Fisher’s exact test was used for between-group comparison of categorical variables. A two-way analysis of variance (ANOVA) test for repeated measurements was used to examine the differences between groups in terms of change in intraoperative variables and VAS scores over time. The comparison of groups at different time points was done with a Mann-Whitney U test or a student t-test, where appropriate. Two-sided p-values <0.05 were considered indications of statistical significance.PatientsOut of 77 patients enrolled in this study, the ESP block failed in one patient, and two patients could not give a proper anamnesis after surgery. These patients were excluded from follow-up. Seventy-four patients were included in the analysis. Demographic characteristics and clinical data are shown in Table Intraoperative assessments2 (p=0.025), and ANI (p=0.001) over time, but not in terms of BIS changes (p=0.444).The mean opioid (remifentanil) amount administered during the operation was 1.9±0.4 mg  in the opioid group. Figure The opioid-free group had significantly higher HR and MAP at baseline; however, at and after 60 minutes, these two parameters were significantly lower in the opioid-free group . Oxygen saturation was lower in the opioid group at and after 60 minutes . ANI scores were significantly higher in the opioid group when compared to the non-opioid group at all time points .Postoperative assessmentsChanges in VAS ScoresFigure Postoperative Opioid RequirementPostoperative intravenous opioid doses administered via patient-controlled analgesia are shown in Table Postoperative RecoveryThe opioid-free group had significantly better QoR-40 scores , and shorter times to mobilization  and oral intake   with controls in patients undergoing VATS in terms of postoperative pain control . AlthougTo the best of our knowledge, to date, only one study has examined the effect of ESPB on postoperative recovery in patients undergoing VATS using the same evaluation tool as the present study (QoR-40) . In thatOpioid-free anesthesia has the potential to reduce the total opioid load not only by avoiding opioids during the operation but also by reducing postoperative opioid needs. Opioids are a special concern due to their untoward effects, including respiratory side effects, particularly for VATS. ESPB is a relatively simple and safe technique, particularly when performed under ultrasound guidance ; thus, iThe study has some limitations. The VAS score is significantly higher at the first 24-hour follow-up in the opioid group compared to the opioid-free group. It cannot be discriminated whether this is due to opioid-induced hyperalgesia or because of the high analgesic effect of the ESPB applied in the opioid-free group. Our postoperative follow-up lasted up to 48 hours, and we did not investigate chronic pain. However, this study was designed to compare the effectiveness of these blocks for acute pain control. Finally, the study is single-centered, and the sample size is relatively small. These are also limitations of the study.The findings of this study suggest that ESPB, when performed as a part of an opioid-free anesthesia protocol in patients undergoing lobectomy with VATS, reduces opioid consumption, improves recovery, reduces opioid-related side effects, and provides better postoperative pain management. Further studies are warranted to better clarify its role as a part of opioid-free anesthesia in VATS.


In-hospital and 30-day mortality are significantly higher in patients who receive vasopressors . Also, analyses of data from 10 studies (n = 3519) revealed that vasopressor use is associated with acute kidney injury . In conclusion, current use of vasopressors in critically ill patients with COVID-19 may be associated with higher in-hospital mortality, 30-day mortality, and incidence rate of acute kidney injury. Further research is required to estimate the correlation of specific vasopressor characteristics  with adverse effects and mortality in this population.Exogenous catecholamines may have pronounced side effects and affect physiological cascades. The aim of this study was to investigate the effect of vasopressors on mortality of critically ill patients with coronavirus disease 2019 (COVID-19). A systematic search of PubMed, Scopus, and ClinicalTrials.gov was conducted for relevant articles until December 2022. Eligibility criteria were randomized controlled and non-randomized trials. The primary outcome was in-hospital and 30-day mortality. The quality of studies was assessed using the Methodological Index for Non-Randomized Studies (MINORS) tool, while paired meta-analysis was used to estimate the pooled risk ratios (RR) along with their 95% Confidence Interval (95% CI). Analyses of 22 studies (The online version contains supplementary material available at 10.1007/s44254-023-00013-7. Mounting evidence suggest that coronavirus disease 2019 (COVID-19) should be perceived as a new entity with its own characteristics and distinct pathophysiology, including complex immuno-inflammatory, thrombotic, and parenchymal derangements . SARS-CoMost critically ill patients with COVID-19 need hemodynamic support that may still be guided by the current, non-covid, surviving sepsis campaign guidelines recommending the use of vasopressors to optimize mean arterial pressure (MAP) and cardiac output and provide adequate organ perfusion –9. Most We therefore performed a systematic review and meta-analysis to investigate the effect of vasopressors on mortality of critically ill patients with COVID-19.The protocol was registered in the PROSPERO international prospective register of systematic reviews on 13 December 2021 (CRD42021297595). This systematic review and meta-analysis was designed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist  randomized controlled trials (RCTs) and observational studies; (2) critically ill patients admitted to the intensive care (ICU) or high dependency unit (HDU), including patients admitted through the Emergency Department (ED); (3) adults (≥ 18 years old) hospitalized primarily for COVID-19; (4) SARS-CoV-2 infection confirmed by reverse transcription polymerase chain reaction test of nasopharyngeal or oropharyngeal samples; and (5) vasopressor The primary outcome was in-hospital and 30-day mortality. Secondary outcome was to investigate (1) the hemodynamic profiles of patients at first measuring point and after six hours ; (2) the number of participants who achieved the target MAP; (3) time to achieve the target MAP; (4) adverse events including arrhythmia, acute myocardial infarction, cardiac arrest, acute mesenteric ischemia, digital ischemia, acute kidney injury (AKI); (5) vasopressor-free days; (6) ICU or HDU length of stay; (7) duration of mechanical ventilation; (8) ventilator free days; (9) hospital length of stay; and (10) all-cause mortality at 90-days.The data from each study were extracted by two independent authors  with a customized format. Any disagreements between the two independent authors were resolved by four other authors . Publication details , study information , hemodynamic profile  at first measuring point and six hours after vasopressor use, the number of participants who achieved the target MAP and time to achieve the target MAP, adverse events, vasopressor-free days, ICU length of stay, hospital length of stay, duration of mechanical ventilation, ventilator-free days, all-cause mortality in all groups at 28 or 30 days, and all-cause mortality at 90 days were extracted in a pre-designed excel spreadsheet. The definition used for AKI and the mortality follow-up timepoints for each study are presented in Additional file The search strategy was intended to explore all available published and unpublished studies from January 2020 to January 2022. A comprehensive initial search was employed in PubMed (MEDLINE), Scopus, and ClinicalTrials.gov databases by two independent investigators  followed by an analysis of the text words contained in Title/Abstract and indexed terms. A second search was conducted by combining free text words  and indexed terms with Boolean operators. Finally, a third search was conducted with the reference lists of all identified reports and articles for additional studies. After the initial data was compiled, a refresh repeat search until December 31, 2022 was performed. Additional file Articles identified for retrieval were assessed by two independent authors  for methodological quality before inclusion in the review using standardized critical appraisal tools. The quality of the included observational studies was assessed using the Methodological Index for Non-Randomized Studies (MINORS) tool , while tI2 indices. When I2 > 50% and/or PQ < 0.10, the random effects model was used, otherwise the fixed effects model was implemented [p < 0.05. All statistical analyses were performed in Review Manager (Rev-Man) [Computer program], Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.A paired meta-analysis was used to estimate the pooled risk ratios (RR) along with their 95% Confidence Interval (95% CI). Based on the presence of statistical heterogeneity, the meta-analysis was conducted according to fixed- or random effect models. The statistical heterogeneity was estimated by the use of the Cochran’s Q and lemented . Funnel lemented , 20. TheAltogether, 1495 relevant citations were identified and screened, while 93 studies were included in our final assessment for possible data extraction , the random-effects model was implemented. Vasopressor use is associated with mortality in patients who received vasopressors compared to those who did not receive vasopressor therapy   did not reveal significant publication bias.Twenty-two out of the 34 included studies provided data on in-hospital mortality in patients who received ividuals , 53, 54.p < 0.0001], HDU , and ICU + HDU , remained statistically significant for higher mortality rates in patients who received vasopressors.We performed subgroup analyses based on the department of admission. The results for all three subgroups, namely ICU .Subgroup analyses were also performed based on the mortality follow-up timepoints. Only the in-hospital and 30-day mortality subgroups had three or more studies that allowed data extraction and analysis. The in-hospital and 30-day mortality were significantly higher in patients who received vasopressors  : 2.29 1.67–3.14); ; p < 0.0No data were identified for the remaining secondary outcomes.vs. random effect); in both cases, the sensitivity analysis confirmed the robustness of the findings. The synthesized results of the present systematic review and meta-analysis together with the results of the sensitivity analysis are depicted in Table A sensitivity analysis was performed for both outcomes based on the implemented meta-analyses model (fixed p = 0.18) did not reveal significant publication bias for the studies included in the AKI analysis. All included studies were observational non-randomized studies with high heterogeneity that does not allow to derive an estimate of overall effect. According to GRADE criteria, the quality of evidence provided by the studies was low.The overall quality of the studies, as assessed by the MINORS tool, ranged between moderate and high. The exact score for each study is available in Additional file Many high-quality RCTs have addressed the effect of vasopressors on the outcomes of non-covid patients, yet their impact in patients with COVID-19 had not been studied so far. The most important finding of this systematic review and meta-analysis is the association between vasopressor therapy and in-hospital mortality, 30-day mortality, and incidence rate of AKI as compared to no vasopressor therapy in critically ill patients with COVID-19. Although these results are based on non-randomized evidence, they raise significant concerns for the routine management of these individuals.The mortality of critically ill patients with COVID-19 remains high , 56. A mOf the 34 studies included in this systematic review and meta-analysis, only four studies provided data on specific vasopressors. The highest mortality rate was observed in patients receiving vasopressin or epinephrine. Although one can appraise that these patients had severe shock necessitating second- and third-line vasopressors , these oAnother intriguing finding is the low mortality rate in patients receiving angiotensin-II as a sole or second-line vasopressor agent. Serpa Neto et al. showed a potentially positive effect of angiotensin-II on blood pressure and fraction of inspired oxygen in COVID-19 patients, but they did not collect data regarding treatment with steroids or other drugs, which may have affected their results . Ofosu-BA meta-analysis of RCTs with non-covid patients reported that vasopressor therapy is not associated with differences in mortality in the overall population, while prophylactic administration in patients with vasodilatory shock may improve survival . In addiIn COVID-19, the progressive hypoxemia initially increases cardiac output and capillary recruitment, which maintain microcirculatory oxygen-extraction capacity by increasing red blood cell availability (silent hypoxia) –70. HoweThis meta-analysis was based on observational studies, while the results are subject to confounding by indication. In addition, due to the lack of RCTs, the synthesis of all the available knowledge on the specific outcomes was difficult. This is an inherent problem to observational studies, and not least considering the difficulties of collecting data during the periods of surges across the globe. Moreover, we could not obtain individual data to reach a minimal level of evidence that could result on relevant findings. Therefore, the effects of different vasopressors may reflect differences in severity and/or practices.Furthermore, most of the included studies were published before November 2021 and thus, we were not able to analyze the data according to COVID-19 surge. In addition, the level of heterogeneity was high; possible reasons are the baseline status of patients, comorbidities, severity of COVID-19, and hospital department, i.e., HDU, ICU, and ED. There were no data for adjusting the resulting odds ratios according to age, comorbidities, the presence of septic shock, or other known factors that affect ICU mortality. Also, most of the secondary outcomes could not be assessed. Another limitation is the heterogeneity of definitions of AKI that were used across different studies. Finally, non-English publications were not included. Therefore, the results of this systematic review and meta-analysis must be interpreted with caution. International registries should collect uniform data to evaluate the effect of vasopressors on mortality and other outcomes in critically ill patients with COVID-19.Current use of vasopressors in critically ill patients with COVID-19 may be associated with higher in-hospital mortality, 30-day mortality, and incidence rate of AKI. The lower mortality rate in patients receiving angiotensin-II as a sole or second-line vasopressor agent is worth noting. Of note, the included studies were observational with high heterogeneity, which does not allow to derive an estimate of overall effect. Randomized controlled trials and translational research are required to estimate the correlation of specific vasopressor characteristics  with adverse effects and mortality in this population.The results of the present systematic review and meta-analysis suggest for early administration of low-dose vasopressors, with or without inodilator agents, in an effort to avoid excessive doses that could have detrimental effect on survival, especially at later disease stages. An alternative second-line vasopressor may be angiotensin-II. However, further immediate research is recommended to elucidate the effects of angiotensin-II and other vasopressors acting through pathways other than the adrenergic. These agents may be associated with a significant increase in survival.A possible explanation for the association of vasopressors with mortality may lie in the microcirculation –77. The vs. non-catecholamine), timingof initiation, and infusion rates of vasopressors in order to develop more specific treatment strategies and integrate a more individualized approach in patients with COVID-19. Although designing and conducting RCTs on vasopressors may be difficult during a disease outbreak, the need for assessing their effect on outcomes of critically ill patients with COVID-19 is imperative. We recommend the use of animal models and the integration of translational research to aid in the identification of the most suitable vasopressor in this population and to better define homogenous target (sub)populations for trials [The present systematic review and meta-analysis included data from observational studies. Further research and well-designed trials are necessary to investigate the effect of the type (catecholamine r trials –85. LargAdditional file 1:Appendix A. PRISMA checklist.Additional file 2: Appendix B. Algorithms used for all databases.Additional file 3: Appendix C1. Definitions used for AKI and mortality follow-up time points. Appendix C2. Angiotensin-related data. Appendix C3. MINORS results for each study.Additional file 4: Appendix D1. Funnel plot for mortality meta-analysis. Appendix D2. Funnel plot for AKI meta-analysis.