Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality among Patients with COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 � 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 �103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7) were included in the primary analysis (median interquartile range age, 62 50-71 years; 237 42.2% women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% 95% CI,-6.6% to 9.8%; odds ratio, 1.06 95% CI, 0.76-1.48; P =.70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% 1-sided 97.5% CI,-� to 3.4%; odds ratio, 1.83 1-sided 97.5% CI, 0.00-5.93), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% 95% CI, 0.4%-3.8%; P =.01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508. © 2021 American Medical Association. All rights reserved

A disturbed state concept-based solution for nonlinear consolidation of soils

This paper proposes a simplified solution for the nonlinear consolidation of soft soils under a wide range of loading using the disturbed state concept. The mechanical properties of soil are stress-dependent, and this affects the soil's compressibility and permeability. However, Terzaghi's conventional theory of consolidation neglects these changes in soil parameters during the consolidation process, which limits its applicability beyond materials with constant parameters. Other sophisticated theories for nonlinear consolidation require advanced calculations that cannot be performed without special programs and codes. The proposed method uses the disturbed state concept to determine the solutions of the nonlinear partial differential equation of consolidation based on the solutions of the linear consolidation partial differential equation in two reference states and a sigmoid form state function for interpolation. The state function is derived using the nonlinear finite difference method. The proposed method accounts for both material nonlinearity arising from changes in the compressibility and permeability of the soil layer and geometrical nonlinearity arising from changes in the thickness of the soil layer. The proposed method adopts the solutions of Terzaghi's theory of consolidation to the solutions of nonlinear consolidation. The results of the proposed method are verified using the results of the nonlinear finite difference method and laboratory data published in the literature. The verification of the results indicates the accuracy of the proposed method

Laboratory and numerical simulation of the effect of wraparound anchorage of reinforcements on the bearing capacity of spread footing

In this research, the effects of the wraparound anchorage on the bearing capacity of a spread footing on sand reinforced by carbon fiber reinforced polymer strips were studied experimentally and numerically. A steel box with the dimensions of 100×100×70 cm was used as a test setup and the spread footing was simulated using a steel plate with the dimensions of 20×20×2.5 cm. Also, a numerical model was developed by FLAC3D software to simulate the physical model for further investigations. Laboratory tests were conducted on unreinforced and reinforced models with and without wraparound anchors with different lengths. The results of these investigations indicated that the effect of the wraparound anchorage on the bearing capacity of the foundation was highly dependent on the return length of the anchor. Its effect on the improvement of the bearing capacity of the foundation was noticeable when the length of the anchor was long enough that the end of the reinforcement placed under the footing. Otherwise, the effect of the wraparound anchor on the improvement of the bearing capacity of the footing was negligible. Depending on the length of the return anchor, two distinct load-settlement behaviors were observed. When the length of the return anchor was not long enough, the bearing capacity of the footing showed some improvement in low settlement levels, but it approached the bearing capacity of the footing with unanchored reinforcements as the settlement was increasing. There was at least 10% improvement in the bearing capacity in this situation. For models with long return anchors, increasing the settlement of the footing increased the bearing capacity of the footing when compared to the behavior of reinforced model without wraparound anchor. The improvement of the bearing capacity of the footing was up to 27% for long anchors depending on the length of the wraparound anchor. The results of the numerical simulations indicated that the wraparound anchorage changed the stress distribution and increased the confinement of the soil elements located under the footing. Increasing the length of the return anchors led to a uniform distribution of the confining pressure under the footing

Glaucoma alters the circadian timing system.

Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC) and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are mediated by a specialized subset of melanopsin expressing RGCs that provide photic input to mammalian endogenous clock in the suprachiasmatic nucleus (SCN). In order to explore the molecular, anatomical and functional consequences of glaucoma we used a rodent model of chronic ocular hypertension, a primary causal factor of the pathology. Quantitative analysis of retinal projections using sensitive anterograde tracing demonstrates a significant reduction (approximately 50-70%) of RGC axon terminals in all visual and non-visual structures and notably in the SCN. The capacity of glaucomatous rats to entrain to light was challenged by exposure to successive shifts of the light dark (LD) cycle associated with step-wise decreases in light intensity. Although glaucomatous rats are able to entrain their locomotor activity to the LD cycle at all light levels, they require more time to re-adjust to a shifted LD cycle and show significantly greater variability in activity onsets in comparison with normal rats. Quantitative PCR reveals the novel finding that melanopsin as well as rod and cone opsin mRNAs are significantly reduced in glaucomatous retinas. Our findings demonstrate that glaucoma impacts on all these aspects of the circadian timing system. In light of these results, the classical view of glaucoma as pathology unique to the visual system should be extended to include anatomical and functional alterations of the circadian timing system

Mapping the daily rhythmic transcriptome in the diabetic retina

Retinal function changes dramatically from day to night, yet clinical diagnosis, treatments, and experimental sampling occur during the day. To begin to address this gap in our understanding of disease pathobiology, this study investigates whether diabetes affects the retina's daily rhythm of gene expression. Diabetic, Ins2Akita/J mice, and non-diabetic littermates were kept under a 12 h:12 h light/dark cycle until 4 months of age. mRNA sequencing was conducted in retinas collected every 4 h throughout the 24 hr light/dark cycle. Computational approaches were used to detect rhythmicity, predict acrophase, identify differential rhythmic patterns, analyze phase set enrichment, and predict upstream regulators. The retinal transcriptome exhibited a tightly regulated rhythmic expression with a clear 12-hr transcriptional axis. Day-peaking genes were enriched for DNA repair, RNA splicing, and ribosomal protein synthesis, night-peaking genes for metabolic processes and growth factor signaling. Although the 12-hr transcriptional axis is retained in the diabetic retina, it is phase advanced for some genes. Upstream regulator analysis for the phase-shifted genes identified oxygen-sensing mechanisms and HIF1alpha, but not the circadian clock, which remained in phase with the light/dark cycle. We propose a model in which, early in diabetes, the retina is subjected to an internal desynchrony with the circadian clock and its outputs are still light-entrained whereas metabolic pathways related to neuronal dysfunction and hypoxia are phase advanced. Further studies are now required to evaluate the chronic implications of such desynchronization on the development of diabetic retinopathy.<br/

Levels of intraocular pressure (IOP) of rats following treatment with Argon laser photocoagulation.

<p>IOP in the operated eyes are compared with that in the unoperated eyes from the same individuals (n = 12). Arrows represent the times of the three laser surgeries. The serial sequence of laser treatments assures a long-term chronic elevation of IOP.</p