vis5.mp4

The refractive solution to the coupling two incident beams to two scattered beams. The left column is the real part of the incident/non-adjoint electric fields, the second column is the real part of the scattered/adjoint fields. The third column is the final permittivity of the medium. The right column shows both field magnitudes, the red channel being the non-adjoint field and the green channel being the adjoint field

vis1.mp4

The diffractive solution to the coupling an incident to a scattered beam. The beam is incident from the lower left at an angle of 45 degrees and scattered to the lower right at an angle of 60 degrees. The upper left panel is the real part of the incident/non-adjoint electric field, the upper right panel is the real part of the scattered/adjoint field, the lower left is the final permittivity of the medium. the lower right panel shows both field magnitudes, the red channel being the non-adjoint field and the green channel being the adjoint field

vis4.mp4

The diffractive solution to the coupling two incident beams to two scattered beams. The left column is the real part of the incident/non-adjoint electric fields, the second column is the real part of the scattered/adjoint fields. The third column is the final permittivity of the medium. The right column shows both field magnitudes, the red channel being the non-adjoint field and the green channel being the adjoint field

vis3.mp4

The refractive solution, with smoothing, to the coupling an incident to a scattered beam. The beam is incident from the lower left at an angle of 45 degrees and scattered to the lower right at an angle of 60 degrees. The upper left panel is the real part of the incident/non-adjoint electric field, the upper right panel is the real part of the scattered/adjoint field, the lower left is the final permittivity of the medium. the lower right panel shows both field magnitudes, the red channel being the non-adjoint field and the green channel being the adjoint field

Additional file 8: Figure S8. of Interleukin-1β signaling in fenestrated capillaries is sufficient to trigger sickness responses in mice

Cx3cr1ΔMyd88-mediated disruption of IL-1β signaling exclusively in microglia does not affect sickness responses. Both Cx3cr1ΔMyd88 (KO) and their Cre−, Myd88 fl/fl littermates (fl/fl) exhibit IL-1β-induced sickness responses. Regardless of genotype IL-1β treatment caused a significant reduction in both overnight (6 pm–6 am) total food intake (FI; A) and change in body weight (ΔBW; B). All values shown are mean ± SEM for group sizes shown in legend. **p < 0.01. (TIFF 123 kb

Additional file 4: Figure S4. of Interleukin-1β signaling in fenestrated capillaries is sufficient to trigger sickness responses in mice

Neurons in the PVN do not exhibit IL-1β-induced nuclear NF-κB. Representative epifluorescent images show that IL-1β causes nuclear localization of NF-κB (green) within the paraventricular nucleus (PVN; A, arrowheads). Despite a high density of neuronal nuclei (NeuN, red; B, arrows), there was no evidence of co-localization (C, n = 3). Scale bars = 50 μm. (TIFF 7122 kb

Additional file 3: Figure S3. of Interleukin-1β signaling in fenestrated capillaries is sufficient to trigger sickness responses in mice

DAPI labeling confirms IL-1β-induced NF-κB nuclear localization. Representative epifluorescent images of NF-κB immunoreactivity (IR; left column) and DAPI labeling of nuclear DNA (middle column) 30 min after treatment demonstrate the change in cellular localization caused by 10 ng intracerebroventricular (ICV) IL-1β. This effect is most obvious in the cuboidal cells of the choroid plexus (ChP), where NF-κB IR is found predominantly in the cytoplasm in sections from vehicle-treated animals (artificial cerebrospinal fluid, aCSF; open arrowhead in A) and concentrated in the nucleus of IL-1β-treated animals (arrowhead in B). Like the ChP, the ependymal cells (C) that form the barrier between the CSF and the brain consistently exhibit NF-κB nuclear localization, serving as an indicator that the animal has been exposed to IL-1β. While there are cells in all tissues, there that do not respond to IL-1β (DAPI-labeled blue nuclei that do not co-label with red NF-κB; right column), puncta of concentrated NF-κB IR overlap DAPI, indicating nuclear localization (filled arrowheads). This is true for all regions of the brain, including the organum vasculosum lamina terminalis (OVLT; D), the subfornical organ (SFO; E), the paraventricular nucleus (PVN; F), and median eminence (ME; G). The high cellular density of the brain, particularly within the OVLT, SFO, and PVN, makes it difficult to distinguish between different cells. Scale bars = 25 μm. (TIFF 2487 kb

Additional file 3: Figure S3. of Amplification and propagation of interleukin-1β signaling by murine brain endothelial and glial cells

Primary microglia and SIM-A9 cells respond to LPS and TNFα. Inflammatory gene expression in A. WT primary microglia and B. SIM-A9 cells that were treated with PBS or LPS (10 ng/mL) for 4 h. n = 4 per group. ***p < 0.001 vs. PBS-treated cells C. Inflammatory gene expression in SIM-A9 cells that were treated with PBS or TNFα (50 ng/mL) for 4 h. n = 4 per group. Data are expressed as mean ± SEM. *p < 0.05, ***p < 0.001 vs. PBS-treated cells. (PDF 468 kb

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

BackgroundTranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding.MethodsWe did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.FindingsBetween July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).InterpretationWe found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial.</div