Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration

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Long-Term Evolution of the Aerosol Debris Cloud Produced by the 2009 Impact on Jupiter

We present a study of the long-term evolution of the cloud of aerosols produced in the atmosphere of Jupiter by the impact of an object on 19 July 2009 (Sánchez-Lavega, A. et al. [2010]. Astrophys. J. 715, L155–L159). The work is based on images obtained during 5 months from the impact to 31 December 2009 taken in visible continuum wavelengths and from 20 July 2009 to 28 May 2010 taken in near-infrared deep hydrogen–methane absorption bands at 2.1–2.3 μm. The impact cloud expanded zonally from ∼5000 km (July 19) to 225,000 km (29 October, about 180° in longitude), remaining meridionally localized within a latitude band from 53.5°S to 61.5°S planetographic latitude. During the first two months after its formation the site showed heterogeneous structure with 500–1000 km sized embedded spots. Later the reflectivity of the debris field became more homogeneous due to clump mergers. The cloud was mainly dispersed in longitude by the dominant zonal winds and their meridional shear, during the initial stages, localized motions may have been induced by thermal perturbation caused by the impact’s energy deposition. The tracking of individual spots within the impact cloud shows that the westward jet at 56.5°S latitude increases its eastward velocity with altitude above the tropopause by 5–10 m s−1. The corresponding vertical wind shear is low, about 1 m s−1 per scale height in agreement with previous thermal wind estimations. We found evidence for discrete localized meridional motions with speeds of 1–2 m s−1. Two numerical models are used to simulate the observed cloud dispersion. One is a pure advection of the aerosols by the winds and their shears. The other uses the EPIC code, a nonlinear calculation of the evolution of the potential vorticity field generated by a heat pulse that simulates the impact. Both models reproduce the observed global structure of the cloud and the dominant zonal dispersion of the aerosols, but not the details of the cloud morphology. The reflectivity of the impact cloud decreased exponentially with a characteristic timescale of 15 days; we can explain this behavior with a radiative transfer model of the cloud optical depth coupled to an advection model of the cloud dispersion by the wind shears. The expected sedimentation time in the stratosphere (altitude levels 5–100 mbar) for the small aerosol particles forming the cloud is 45–200 days, thus aerosols were removed vertically over the long term following their zonal dispersion. No evidence of the cloud was detected 10 months after the impact

Case report: acute care management of severe opioid withdrawal with IV fentanyl

Background An increasing number of individuals who use drugs in North America are preferentially consuming fentanyl over other opioids. This has significant consequences on the treatment and management of opioid use disorder (OUD) and its concurrent disorders, especially in acute care if opioid requirements are not met. Case presentation We present a patient with severe OUD and daily injection of fentanyl, admitted to hospital for management of acute physical health issues. Due to high opioid requirements and history of patient-initiated discharge, intravenous fentanyl was administered for treatment of opioid withdrawal, and management of pain, which supported continued hospitalization for acute care treatment and aligned with substance use treatment goals. Conclusion This case demonstrates that intravenous fentanyl for management of OUD in hospital can be a feasible approach to meet opioid requirements and avoid fentanyl withdrawal among patients with severe OUD and daily fentanyl use, thereby promoting adherence to medical treatment and reducing the risk of patient-initiated discharge. There is an urgent need to tailor current treatment strategies for individuals who primarily use fentanyl. Carefully designed research is needed to further explore the use of IV fentanyl for acute care management of severe opioid withdrawal in a hospital setting.Medicine, Faculty ofNon UBCAnesthesiology, Pharmacology and Therapeutics, Department ofCritical Care Medicine, Division ofPsychiatry, Department ofReviewedFacultyResearche

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics