The introduction of a bridge element to covalently ring-lock the neighboring aryl or heteroaryl groups connected by a single bond has led to a variety of fascinating multifused ladder-type structures. Here, we have designed a new series of 2H-pyran containing tetracyclic dithienocyclopentapyran compounds (MMA1 to MMA3). Long conjugation at end-capped of designed systems enhances the power conversion efficiencies of non-fullerene-containing organic solar cells. Different geometric parameters of designed systems have been examined through density functional theory and time-dependent density function theory. Designed molecules expressed high absorption maxima values with a reduced energy bandgap. Open circuit voltage along with transition density matrix analysis recommended that charge transfer occurs from lower energy orbitals to higher energy orbitals. Reorganization energy analysis also suggested high charge mobility occurs from donor polymer to acceptor molecules. Results of all parameters advocated that designed molecules are potential candidates for high-performance organic solar cells.

We present two cases of nine and twenty-seven years old girls with recurrence of immature teratoma after an incomplete surgical staging. In both cases, there were huge abdominopelvic masses despite decrease in tumor markers with chemotherapy. Complete surgical resection of these masses was done, and histopathology showed only mature teratoma.

The primary sources of dissolved inorganic carbon (DIC) in water are carbonate materials and CO2 produced during the biological processing of organic matter. The application of carbon isotope techniques to terrestrial and aquatic ecosystems can accurately elucidate carbon fluxes and other carbon cycle processes in these systems. Lake ecosystems on the Qinghai-Tibetan Plateau are fragile and sensitive to changes in climate and environment. This study explored the relationship between the carbon isotopic composition (δ13C) of the DIC (δ13CDIC) in the Genggahai Lake, the lake environment, and the climate of the watershed based on the observed physicochemical parameters of water in areas with different types of submerged macrophyte communities, combined with changes in the temperature and precipitation during the same period. Overall, the δ13CDIC of the Genggahai Basin exhibited a large range of values, with an average δ13CDIC for inflowing spring water (δ13CDIC-I) of –11.1 ‰, which was the most negative, followed by an average δ13CDIC value of –10.8 ‰ for that from the Shazhuyu River (δ13CDIC-R) and an averageδ13CDIC value of –6.91 ‰ for lake water (δ13CDIC-L). Variations in the photosynthetic activity intensity of different aquatic plants yield significantly changing δ13CDIC-L values in areas with varied aquatic plant communities. Hydrochemical observations revealed that δ13CDIC-I and aquatic plant photosynthesis primarily affected the differences in the δ13CDIC-L values of the Genggahai Lake, thereby identifying them as the key components of the lake carbon cycle.

In semiarid to arid regions of the western U. S., the availability and variability of river flow are highly subject to shifts in snow accumulation and ablation in alpine watersheds. This study aims to examine how shifts in snowmelt rate (SMR) and snow continuity, an indicator of the consistent existence of snow on the ground, affect snow-driven streamflow dynamics in three alpine watersheds in the U.S. Great Basin. To achieve this end, the coupled hydro-ecological simulation system (CHESS) is used to simulate river flow dynamics and multiple snow metrics are calculated to quantify the variation of snowmelt rate and snow continuity, the latter of which is measured, respectively, by snow persistence (SP), snow residence time (SRT) and snow season length (SSL). Then, a new approach is proposed to partition streamflow into snow-driven and rain-driven streamflow. The statistical analyses indicate that the three alpine watersheds experienced a downward trend in SP, SRT, SSL and SMR during the study period of 1990-2016 due to regional warming. As a result, the decrease in SMR and the decline in snow continuity shifted the day of 25% and 50% of the snow-driven cumulative discharge as well as peak discharge toward an earlier occurrence. Besides, the magnitudes of snow-driven annual streamflow, summer baseflow and peak discharge also decreased due to the declined snow continuity and the reduced snowmelt rate. Overall, by using multiple snow and flow metrics as well as by partitioning streamflow into snow-driven and rain-driven flow via the newly proposed approach, we found that snowmelt rate and snow continuity determine the streamflow hydrographs and magnitudes in the three alpine watersheds. This has important implications for water resource management in the snow-dominated region facing future climate warming given that warming can significantly affect snow dynamics in alpine watersheds in semiarid to arid regions.

Lateral saturated soil hydraulic conductivity, Ks,l, is the soil property governing subsurface water transfer in hillslopes, and the key parameter in many numerical models simulating hydrological processes both at the hillslope and catchment scales. Likewise, the hydrological connectivity of lateral flow paths plays a significant role in determining the intensity of the subsurface flow at various spatial scales. The objective of the study is to investigate the relationship between Ks,l and hydraulic connectivity at the hillslope spatial scale. Ks,l was determined by the subsurface flow rates intercepted by drains, and by water table depths observed in a well network. Hydraulic connectivity of the lateral flow paths was evaluated by the synchronicity among piezometric peaks, and between the latter and the peaks of drained flow. Soil moisture and precipitation data were used to investigate the influence of the transient hydrological soil condition on connectivity and Ks,l. It was found that the higher was the synchronicity of the water table response between wells, the lower was the time lag between the peaks of water levels and those of the drained subsurface flow. Moreover, the most synchronic water table rises determined the highest drainage rates. The relationships between Ks,l and water table depths were highly non-linear, with a sharp increase of the values for water table levels close to the soil surface. Estimated Ks,l values for the full saturated soil were in the order of thousands of mm h-1, suggesting the activation of macropores in the root zone. The Ks,l values determined at the peak of the drainage events were correlated with the indicators of synchronicity. The sum of the antecedent soil moisture and of the precipitation was correlated with the indicators of connectivity and with Ks,l. We suggest that, for simulating realistic processes at the hillslope scale, the hydraulic connectivity could be implicitly considered in hydrological modelling through an evaluation of Ks,l at the same spatial scale.

We report a case of renal cell carcinoma metastasis to the duodenum.

Against the backdrop of the second wave of COVID-19 pandemic in India that started in March 2021, we have monitored the spike (S) protein mutations in all the reported (GISAID portal) whole genome sequences of SARS CoV-2 circulating in India from 1 st January 2021 to 31 st August 2021. In the 43,102 SARS-CoV-2 genomic sequences analysed, we have identified 24, 260 mutations in the S protein, based on which 265 pango lineages could be categorised. The dominant lineage in most of the 28 states of India and its 8 union territories was B.1.617.2 (the delta variant). However, the states Madhya Pradesh, Jammu & Kashmir, and Punjab had B.1.1.7 (alpha variant) as the major lineage, while the Himachal Pradesh state reported B.1.36 as the dominating lineage. A detailed analysis of various domains of S protein was carried out for detecting mutations having a prevalence of >1%; 70, 18, 7, 3, 9, 4, and 1 (N=112) such mutations were observed in the N -terminal domain, receptor binding domain, C -terminal domain, fusion peptide region, heptapeptide repeat (HR)-1 domains, signal peptide domain, and transmembrane region, respectively. However, no mutations were recorded in the HR-2, and cytoplasmic domains of the S protein. Interestingly, 13.39% (N=15) of these mutations were reported to increase the infectivity and pathogenicity of the virus; 2%(N=3) were known to be vaccine breakthrough mutations; and 0.89%(N=1) were known to escape neutralising antibodies. Biological significance of 82% (N=92) of the reported mutations is yet unknown. As SARS-CoV-2 variants are emerging rapidly, it is critical to continuously monitor local viral mutations to understand national trends of virus circulation. This can tremendously help in designing better preventive regimens in the country, and avoid vaccine breakthrough infections.

To exploit the full material potential of short fibre reinforced PA6T/6I, specific component calculations including aniso- tropic material behaviour is necessary. For this, different failure criteria and fatigue models are used to describe the behaviour during a component service life. This paper deals with the determination and consideration of fibre orientations for failure criteria and fatigue calculations. Therefore, a novel method to determine fibre orientation (FO) distributions across injection moulded plates, is proposed. The developed method allows a forecast of FOs for different specimen extraction positions and angles on injection moulded plates by using only a few measured reference points. As a result, fatigue models can be calibrated with the strength values and the corresponding FO, calculated for fracture position. The performed tests show a non-negligible influence of failure positions, due to fibre orientation distributions along the specimens. So, the FO determination method delivers an improvement in strength values estimation.

Background: Myocardial protection in reoperations in cardiac surgery is extremely difficult in patients with previous coronary surgery and a working LIMA-LAD graft, and it largely determines the outcome of surgery and long-term prognosis. We use a the method of percutaneous angiographic balloon LIMA occlusion and cardioplegic arrest. Aims: The aim of this study was to compare the data of patients with angiographic balloon LIMA-occlusion and those without occlusion in operations related to PVE, and previous coronary surgery with permeable LIMA graft, determining the degree of safety and benefits of method. Study design and Methods: A total of 20 patients undergoing surgery for prosthesis valve endocarditis with patent LIMA-LAD graft were analyzed retrospectively. We divide the patients into 2 groups. Group A patients - with LIMA occlusion and Group B patients - without LIMA occlusion). The pre-, intra- and postoperative results were compared and the degree of safety and benefits of the application of the method were studied. Results: 80% of patients in group A needed only dopamine infusion and 20% needed the addition of a second catecholamine (Adrenaline) at the end of CPB. In group B, the need for double catecholamine maintenance is in 50% of patients. The need for implantation of an intra-aortic balloon pump due to refractory heart failure was registered in 10% of patients in group A and in 20% of patients in group B. It was found that the average duration of mechanical ventilation in group A is 10.5 hours postoperatively, and in group B - 12.5 hours. The mean duration of catecholamine infusion in both groups was 3 days. The average stay in intensive care is shorter for patients in Group A - 2.5 days, and in Group B is 3.5 days. In terms of survival - mortality in the group with LIMA occlusion is 0%, while in the group without LIMA occlusion is 20%. Conclusion: Our reported results from the use of the LIMA balloon occlusion method in patients with prosthetic valve endocarditis who are high-risk and complicated patients and nevertheless the mortality in this group studied by us is 0% and no serious complications of the applied method have been registered. Therefore, we believe that the angiographic balloon LIMA occlusion is a reliable, easily applicable and relatively safe technique that improves the surgical results and prognosis of patients in need of reoperative cardiac surgery.

The effect of the presence of a deuterium (D) or tritium (T) isotope bonded to the alpha carbon of glycine is determined without the need to apply external forces e.g. electric fields or using normal mode analysis. Isotopic effects were accounted for using the mass-dependent diagonal Born-Oppenheimer energy correction (DBOC) at the CCSD level of theory. We calculated the stress tensor trajectories of the dominant C-N bond within next generation quantum theory of atoms in molecules (NG-QTAIM). S-character chirality was discovered using the stress tensor trajectories, instead of the Cahn–Ingold–Prelog (CIP) rules, for ordinary glycine. The S-character chirality was preserved after the substitution of the H on the alpha carbon for a D isotope but transformed to R-character chirality after replacement with the T isotope. This reversal of the chirality depending on the presence of a single D or T isotope bound to the alpha carbon adds to the debate on the nature of the extraterrestrial origins of chirality in simple amino acids. We demonstrate that NG-QTAIM is a promising tool for understanding isotopic induced electronic charge density changes, useful in analysis of infrared (IR) or circular dichroism (CD) spectra explaining changes in mode couplings and bands intensities or sign.

1. Harmful algal blooms are increasing in both severity and frequency across the globe. Many bloom-forming species are capable of vertical motility and colony formation. The cyanobacterium Microcystis aeruginosa is a common example of such a species, yet current models poorly predict vertical distributions of M. aeruginosa. 2. To couple the hydrodynamics, buoyancy, and the colony dynamics of Microcystis, we present a system of one-dimensional advection-diffusion-aggregation equations with Smoluchowski aggregation terms. 3. Results indicate Smoluchowski aggregation accurately describes the colony dynamics of M. aeruginosa. Further, transport dynamics are strongly dependent on colony size, and aggregation processes are highly sensitive to algal concentration and wind-induced mixing. Both of these findings have direct consequences to harmful algal bloom formation. 4. While the theoretical framework outlined in this manuscript was derived for M. aeruginosa, both motility and colony formation are common among bloom-forming algae. As such, this coupling of vertical transport and colony dynamics is a useful step for improving forecasts of surface harmful algal blooms.

The processes governing soil bacteria biogeography are still not fully understood. It remains unknown how the importance of environmental filtering and dispersal differs between bacterial taxonomic and functional biogeography, and whether their importance is scale-dependent. We sampled soils at 195 plots across the Tibet plateau, with distances among plots ranging from 20 m to 1 550 km. Taxonomic composition of bacterial community was characterized by 16S amplicon sequencing, and functional community composition by qPCR targeting 9 functional groups involved in N dynamics. Twelve climatic and soil characteristics were also measured. Both taxonomic and functional dissimilarities were more related to environmental dissimilarity than geographic distance. Taxonomic dissimilarity was mostly explained by soil pH and organic matter, while functional dissimilarity was mostly linked to moisture, temperature and N, P and C availabilities. The roles of environmental filtering and dispersal were, however, scale-dependent and varied between taxonomic and functional dissimilarities, with distance affecting taxonomic dissimilarity over short distances (<~300 km) and functional dissimilarity over long distances (>~600 km). The importance of different environmental predictors varied across scales more for functional than taxonomic dissimilarity. Our results demonstrate how biodiversity dimension (taxonomic versus functional) and spatial scale strongly influence the conclusions derived from bacterial biogeography studies.

In this paper, we investigate the stability and bifurcation of a discrete-time prey-predator system which is subject to an Allee effect on prey population. It is concluded that the system undergoes flip and Neimark- Sacker bifurcations in a small neigborhood of the unique positive fixed point which depends on the number of prey-predator. The chaotic behavior that emerges with Neimark-Sacker bifurcation is controlled by the OGY method and hybrid control method. Moreover, the numerical simulations are done to demonsrate the theoratical results.

Aim: The effect of the Dutch nationwide adjustment of reduced 6-TGN target values (from 600-1200 pmol/8x108 RBC to 320-630 pmol/8x108 RBC) on toxicity and clinical outcome of thiopurine treatment in patients with inflammatory bowel disease (IBD) has not yet been established. Therefore the authors determined the incidence of toxicity-induced discontinuations and efficacy at both target concentrations. Methods: This retrospective study was performed in IBD patients treated with azathioprine or mercaptopurine. Two groups were defined: the former target (FT) group with target concentrations of 600-1200 pmol/8x10^8 RBC and the adjusted target (AT) group with target concentrations of 320-630 pmol/8x10^8 RBC. Patients were followed for maximum 52 weeks or until discontinuation of thiopurine therapy. Data were collected from the local hospital electronic health software of Rijnstate Hospital. Results: 151 patients were included, 76 in the FT group and 75 in the AT group. At week 52, 100 out of 150 patients (66%) of the total population discontinued thiopurine therapy. Forty-eight of this discontinuations were due toxicity (48%). The estimated cumulative incidence of toxicity was higher in the FT group compared to the AT group (47% and 35% respectively, p=0.25). No loss of efficacy was seen in the AT group. Conclusion: Reduction of the target range may lead to less toxicity induced discontinuations. In addition, this study did not find any indication that the reduction of the target range diminished efficacy.

Building on the work in [1], this paper shows how Conformal Geometric Algebra (CGA) can be used to model an arbitrary two-port scattering matrix as a rotation in four dimensional Minkowski space, known as a spinor. This spinor model plays the role of the wave-cascading matrix in conventional microwave network theory. Techniques to translate two-port scattering matrix in and out of spinor form are given. Once the translation is laid out, geometric interpretations are given to the physical properties of reciprocity, loss, and symmetry and some mathe- matical groups are identified. Methods to decompose a network into various sub-networks, are given. An example application of interpolating a 2-port network is provided demonstrating an advantage of the spinor model. Since rotations in four dimensional Minkowski space are Lorentz transformations, this model opens up the field of network theory to physicists familiar with relativity, and vice versa.

Tristan Boam1, Bethan G Rogoyski2, Melissa Gabriel3, Paul D Losty4Department of Paediatric Surgery, Leicester Royal Infirmary, Leicester, UKLeicester School of Allied Health Sciences, De Montfort University, Leicester, UKDepartment of Urology, Norfolk and Norwich Hospital, Norwich, UKAlder Hey Children’s Hospital NHS Foundation Trust, School of Health and Life Science, University of Liverpool, UK

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors in childhood. Cancer predisposition syndromes (CPS) are increasingly recognized as the underlying cause for a number of pediatric malignancies and up to 40% of PPGL are currently thought to be associated with a hereditary predisposition1,2. With the increasingly widespread availability of functional molecular imaging techniques, nuclear medicine imaging modalities such as 18F-FDG-PET/CT, 123I-MIBG SPECT/CT, and 68Ga-DOTATATE PET/CT now play an essential role in the staging, response assessment and determination of suitability for targeted radiotherapy in patients with PPGL. Each of these imaging modalities targets a different cellular characteristic, such as glucose metabolism (FDG), norepinephrine transporter expression (MIBG), or somatostatin receptor expression (DOTATATE), and therefore can be complementary to anatomic imaging and to each other. Given the recent FDA approval3 and increasing use of 68Ga-DOTATATE for imaging in children4, the purpose of this article is to use a case-based approach to highlight both the advantages and limitations of DOTATATE imaging as it compares to current radiologic imaging techniques in the staging and response assessment of pediatric PPGL, and to offer a decision algorithm for the use of functional imaging that can be applied to PPGL, as well as other neuroendocrine malignancies.

We study the role of symmetries in control systems by means of geometric algebra approach. We discuss two specific control problems on Carnot group of step 2 invariant with respect to the action of$SO(3). We understand geodesics as curves in suitable geometric algebras which allows us to asses an efficient algorithm for local control.

In this paper, we consider the Cauchy problem of the compressible quantum Navier-Stokes equations with damping in R3. We first assume that the H3-norm of the initial data is sufficiently small while the higher derivative can be arbitrarily large, and prove the global existence of smooth solutions. Then the decay estimate of the solution is derived for the initial data in a homogeneous Sobolev space or Besov space with negative exponent. In addition, the usual Lp−L2(1 ≤ p ≤ 2) type decay rate is obtained without assuming that the Lpnorm of the initial data is sufficiently small.

In this study, a combined low and high cycle fatigue (CCF) life prediction model, which considers the crack closure effect (CCE) of micro-defects, is proposed based on the continuous damage mechanics. The CCF life prediction model is decomposed into three sub-models: the low cycle fatigue (LCF), high cycle fatigue (HCF) under the maximum stress of LCF (HCFLM), and their coupled damage models. The CCE is considered by taking one CCE parameter into the HCFLM sub-model. The experimental CCF data of K403 full-scale turbine blades under different vibration stresses is used to verify the accuracy of the proposed model to compare with other life prediction models. The prediction life from the proposed model falls within the 2 times of scatter band compared with the experimental results. Further, there are the different damage evolution forms at different vibration stresses. When the vibration stress is below 64.48MPa, the CCF damage mainly is caused by the LCF damage. However, while the vibration stress is higher than 64.48MPa, the HCFLM damage plays a major role in the CCF damage accumulation, and it is predicted that the CCF damage of the first stage serration on the K403 turbine blades is mainly from LCF.

Three-dimensional (3D) bioprinting shows great potential for autologous vascular grafts due to its simplicity, accuracy, and flexibility. 6mm diameter vascular grafts are used in clinic. However, producing small-diameter vascular grafts are still an enormous challenge. Normally, sacrificial hydrogels are used as temporary lumen support to mold tubular structure which will affect the structure’s stability. In this study, we develop a new bioprinting approach to fabricating small-diameter vessel using two-step crosslinking process. ¼ lumen wall of bioprinted gelatin mechacrylate (GelMA) flat structure is exposed to ultraviolet (UV) light briefly for having certain strength, while ¾ lumen wall shows as concave structure remained uncrosslinked. Pre-crosslinked flat structure is merged towards the uncrosslinked concave structure. Two individual structures will be combined tightly into an intact tubular structure by receiving more UV exposure time. Complicated tubular structures are constructed by these method. Notably, the GelMA-based bioink loaded with smooth muscle cells (SMCs) are bioprinted as the outer layer and human umbilical vein endothelial cells (HUVECs) are seeded onto the inner surface. A bionic vascular vessel with dual layers is fabricated successfully and keeps good viability, and functionality. This study may provide a novel idea for fabricating biomimetic vascular network or other more complicated organs.

Title: Food protein-induced enterocolitis syndrome caused by scallopAuthors: Yuka Okura, Yutaka Takahashi, and Ichiro Kobayashi.Institutional affiliation: Department of Pediatrics, KKR Sapporo Medical Center, Sapporo, JapanRunning title: FPIES caused by scallopCorresponding author: Yuka Okura, KKR Sapporo Medical Center, Department of Pediatrics, 6-3-40, Hiragishi 1-jo, Toyohira-ku, Sapporo, 062-0931, JapanPhone: 81-11-822-1811; Facsimile: 81-11-841-4572; E-mail; okura@kkr-smc.comWord count: 973 wordsTables: 0Figures: 0

A document by Laura Sonneveld, written on Authorea.

Tocilizumab for reduction of mortality in severe COVID-19 patients: how should we GRADE it?Vladimir TrkuljaVladimir Trkulja, MD, PhDDepartment of PharmacologyZagreb University School of MedicineŠalata 1110000 Zagreb, Croatiae-mail: vladimir.trkulja@mef.hrNumber of words: 799Number of figures/tables: 1To the Editor,A recent systematic review/meta-analysis 1 of randomized trials (RCTs) of tocilizumab (plus standard of care [SoC] vs. SoC w/wo placebo) in severe COVID-19 patients was a pleasure to read owing to a clear presentation of a thorough approach to data (e.g., sensitivity analyses, accounting for corticosteroid use, need for mechanical ventilation [MV] at baseline). Authors assigned high quality (certainty) GRADE levels to the evidence of efficacy in reduction of mortality overall (10 RCTs) and in patients without MV at baseline (data from 9 RCTs), and reduction of incident MV (10 RCTs). The grading was based on fixed-effect pooling, likely owing to low inconsistency index (I2) and closely similar fixed-effect and random-effects estimates1. It is this point that deserves a few comments. Conceptually, fixed-effect meta-analysis of RCTs in medicine is rarely justified, since the underlying assumption is practically inevitably violated due to variety of elements contributing to clinical heterogeneity2. The authors1 presented a range of differences in trial designs (e.g., one or repeated tocilizumab dose, more or less use of concomitant corticosteroids, differences in proportion of subjects on MV). When variance across trials is low, fixed and random-effects estimates are numerically close/identical, but the conceptual differences remain. Again, conceptually, the random-effects method is a preferred approach2 (regardless of numerical closeness of fixed/random estimates) and the choice (fixed/random) should not be based on the heterogeneity estimates2. At this point, the issue of the choice of the variance (τ2) estimator should be mentioned. A number of estimators have been explored: performance depends on the nature of the outcome, may vary across trial sizes, depends on the differences in size of included trials, and is problematic when the number of studies is lowe.g.,2-5. Variance reflects on the assigned trial weights and measures of uncertainty about the pooled estimate. While no τ2 estimator is ideal 2-5, it has been suggested that the Paule-Mandel (PM) estimator performs better than the common DerSimonian-Laird estimator for binary outcomes3.Another point to consider is the method to calculate confidence intervals (CIs) around the pooled estimate. While not without certain limitations 6, the Hartung-Knapp-Sidik-Jonkman (HKSJ) method has been repeatedly shown (under variety of scenarios) to result in more adequate coverage probability than the standard method4,7. Figure 1A re-creates meta-analysis (data presented by the authors1) on mortality across the 10 RCTs (all subjects) – it is only that it uses PM variance estimator and HKSJ correction: random-effects estimate suggests that the mean of the distribution of the effects is 0.88 (as reported1), but the CIs extend to 1.04, suggesting that it includes also effects that are somewhat above unity. It also provides prediction intervals (wider) - the best illustration of heterogeneity2,8. When viewed from the present standpoint, data indicate a non-trivial level of imprecision and heterogeneity. The authors themselves reported apparent differences (mortality reduction vs. no reduction) between estimates based on RCTs with a high proportion vs. low proportion of patients concomitantly treated with corticosteroids 1(or those generated accounting only for corticosteroid-treated vs. not treated patients, but such data were very scarce1): so, there is apparent inconsistency of the estimates across clinical settings. As re-created in Figure 1B-C, there was a tendency of reduced mortality in trials with a high proportion of patients co-treated with corticosteroids (corticosteroid treatment regimen likely variable), but with quite some imprecision and heterogeneity; and no such tendency with “low corticosteroid use”. Similarly, in patients not on MV at baseline, there was a consistent reduction in mortality risk across trials with a high proportion of steroid co-treated patients, but not in trials with a low proportion of co-treated patients (Figure 1D-E). There was also a consistent reduction of risk of incident MV in trials with a high proportion of corticosteroid co-treated patients (Figure 1F), whereas the estimate in trials with “low steroid use” is burdened with heterogeneity and imprecision (Figure 1G).Considering the above, if one were to assign a GRADE level9 to evidence of benefit of tocilizumab in severe COVID-19 patients based on the 10 RCTs addressed in the published meta-analysis1, then the following seems reasonable: a) considering (indiscriminately) all 10 RCTs (and all patients), certainty about reduced mortality is closer to “low/moderate” then to “high” due to imprecision (CIs 0.75-1.04) and heterogeneity/inconsistency; b) data on the effect of tocilizumab+corticosteroid combination that could be extracted from the 10 RCTs are scarce. Trials with high vs. low concomitant use of corticosteroids could be perceived as a proxy, but this is indirect, suggestive and not conclusive evidence. Therefore, while the effects of tocilizumab on the risk of incident MV and mortality in patients not on MV at baseline in trials with a high proportion of corticosteroid co-treated patients were consistent and reasonably precisely estimated, certainty about the benefit of tocilizumab (on top of corticosteroids; regimen?) in this setting is at best moderate/low.ReferencesVela D, Vela-Gaxha Z, Rexhepi M, Olloni R, Hyseni V, nallbani R. Efficacy and safety of tocilizumab versus standard of care/placebo in patients with COVID-19; a systematic review and meta-analysis of randomized controlled trials. Br J Clin Pharmacol . 2021; doi: 10.1111/bcp.15124.Higgins JPT, Thomson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. J R Statist Soc A . 2009; 172(Pt1):137-159.Veroniki AA, Jackson D, Viechtbauer W, Bender R, Bowden J, Knapp G, Kuss O, Higgins JPT, Langan D, Salanti G. Methods to estimate the between-study variance and its uncertainty in meta-analysis. Res Synth Methods . 2016;7(1): 55-79.Langan D, Higgins JPT, Jakson D, Bowden J. Veroniki AA, Kontopantelis E, Viechtbauer W, Simmonds M. A comparison of heterogeneity variance estimators in simulated random-effects meta-analyses. Res Synth Methods. 2019; 10(1):83-98.IntHout J, Ioannidis JPA, Borm GF, Goeman JJ. Small studies are more heterogeneous than large ones: a meta-meta-analysis. J Clin Epidemiol . 2015; 68(8):860-869.Jakson D, Law M, Rucker G, Schwarzer G. The Hartung-Knapp modification for random-effects meta-analysis: a useful refinement but are there any residual concerns? Stat Med . 2017; 36(25):3923-3934.IntHout J, Ioannidis JPA, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.BMC Med Res Methodol . 2014; 14:25 doi:10.1186/1471-2288-14-25.IntHout J, Ioannidis JPA, Rovers MM, Goeman JJ. Plea for routinely presenting prediction intervals in meta-analysis. BMJ Open . 2016; 6:e010247 doi: 10.1136/bmjopen-2015-010247Guyatt GH, Oxman, AD, Vist GE, Kurz R, Falck-Ytter Y, Schunemann HJ. GRADE: what is “quality of evidence” and why is it important to clinicians. BMJ . 2008;336(7651):995-998.Balduzzi S, Rucker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health . 2019; 22(4):153-160.Figure 1 . Re-creation of the published meta-analysis1 using data provided in the published figures: the difference is in that the present estimates are generated using the Paule-Mandel variance estimator (Q-profile method for variance estimate confidence intervals) instead of the DerSimonian-Laired method available in the RevMan software used by the authors1, and Hartung Knapp Sidik Jonkman correction for random effects (see text for explanation). Panel A corresponds to published1Figure 1, panels B and C correspond to published1supplemental Figure S4. Published meta-analysis1 does not include figures that would correspond to panels D-G. Panels E and G are reduced to summaries for brevity. Note that in all meta-analyses point-estimates of I2 and τ2 were low, but the upper limits of their confidence intervals were rather high, particularly when only 4 RCTs were included (except in panel F with highly consistent results across trials). “High%” or “low %” steroid use refers to trials (as presented in the published meta-analysis1) in which >50% or <50% of the patients were co-treated with corticosteroids. Meta-analyses were performed using packagemeta 10 in R.MV – mechanical ventilation; RCT – randomized controlled trial; SoC – standard of care